VCV001706561.2 - ClinVar

NM_000939.4(POMC):c.-21+1G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000939.4(POMC):c.-21+1G>A

Variation ID: 1706561 Accession: VCV001706561.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 25168497 (GRCh38) [ NCBI UCSC ] 2: 25391366 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 24, 2022	Sep 24, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000939.4:c.-21+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001035256.3:c.-71+1G>A		splice donor
NM_001319204.2:c.-101+1G>A		splice donor
NM_001319205.2:c.-51+1G>A		splice donor
NC_000002.12:g.25168497C>T
NC_000002.11:g.25391366C>T
NG_008997.1:g.5194G>A
NG_050903.1:g.144C>T

... more HGVS ... less HGVS

Protein change

Other names

NG_008997.1(NM_001035256.3):c.-71+1G>A

Canonical SPDI

NC_000002.12:25168496:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on transcription; Variation Ontology [ VariO:0149]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LOC108167315	-	-	-	GRCh38	-	13
POMC		-	-	GRCh38 GRCh37	170	227

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Obesity due to pro-opiomelanocortin deficiency	Pathogenic (1)	no assertion criteria provided	-	RCV002285116.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	no assertion criteria provided Method: clinical testing, in vitro	Obesity due to pro-opiomelanocortin deficiency (Autosomal recessive inheritance) Affected status: not applicable, yes Allele origin: germline, not applicable	Laboratory of Functional Genomics, Research Centre for Medical Genetics Accession: SCV002573791.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Publications: DOI: 10.1210/clinem/dgac397 DOI: 10.1210/clinem/dgac397 Observation 1: Number of individuals with the variant: 21 Sex: mixed Ethnicity/Population group: Perm Tatar Geographic origin: Perm region, Russia Comment on evidence: We observed seven unrelated patients who shared a novel homozygous variant in the 5′-untranslated region of the POMC gene. Their parents were heterozygous carriers of … (more) We observed seven unrelated patients who shared a novel homozygous variant in the 5′-untranslated region of the POMC gene. Their parents were heterozygous carriers of variant c.-71-1G>A. (less) Observation 2: Result: For functional analysis we fused POMC 5'-UTR with Renilla luciferase so that the luciferase started with the ATG-codon of the POMC open reading frame. RT-PCR of RNA isolated from cells transfected with plasmids containing WT POMC 5'-UTR and with c.-71+1G>A variant showed the absence of any PCR-products, while we observed a correct splicing of the wild-type POMC transcript. qPCR experiments revealed 20 times lower mRNA expression of Renilla luciferase in the Mut sample compared to the WT. Additionally, we performed dual luciferase reporter assay of transfected HEK293T cells, and we showed that c.-71+1G>A variant led to a significant depletion of luciferase protein level. We performed RNA-seq analysis of transfected cells to directly confirm the effect c.-71+1G>A variant on mRNA expression. In the wild-type sample, we observed a high expression level of wild-type isoform with two exons. In the mutant sample, we did not observe any expression of POMC-hRluc transcript. RNA-seq coverage of this region did not exceed the background transcription from the plasmid observed for the intergenic region between POMC-hRluc and hluc+ genes.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on transcription (VariO:0149)	Method not provided	For functional analysis we fused POMC 5'-UTR with Renilla luciferase so that the luciferase started with the ATG-codon of the POMC open reading frame. RT-PCR of RNA isolated from cells transfected with plasmids containing WT POMC 5'-UTR and with c.-71+1G>A variant showed the absence of any PCR-products, while we observed a correct splicing of the wild-type POMC transcript. qPCR experiments revealed 20 times lower mRNA expression of Renilla luciferase in the Mut sample compared to the WT. Additionally, we performed dual luciferase reporter assay of transfected HEK293T cells, and we showed that c.-71+1G>A variant led to a significant depletion of luciferase protein level. We performed RNA-seq analysis of transfected cells to directly confirm the effect c.-71+1G>A variant on mRNA expression. In the wild-type sample, we observed a high expression level of wild-type isoform with two exons. In the mutant sample, we did not observe any expression of POMC-hRluc transcript. RNA-seq coverage of this region did not exceed the background transcription from the plasmid observed for the intergenic region between POMC-hRluc and hluc+ genes.	Laboratory of Functional Genomics, Research Centre for Medical Genetics Accession: SCV002573791.1	Publications DOI: 10.1210/clinem/dgac397

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
-	-	-	-	DOI: 10.1210/clinem/dgac397

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000939.4(POMC):c.-21+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...