NM_017951.5(SMPD4):c.345+1G>T AND Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000853215.6

Allele description [Variation Report for NM_017951.5(SMPD4):c.345+1G>T]

NM_017951.5(SMPD4):c.345+1G>T

Gene:

SMPD4:sphingomyelin phosphodiesterase 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q21.1

Genomic location:

Preferred name:

NM_017951.5(SMPD4):c.345+1G>T

HGVS:

NC_000002.12:g.130173278C>A
NG_053070.1:g.14473G>T
NM_001171083.2:c.244-383G>T
NM_017751.4:c.462+1G>T
NM_017951.5:c.345+1G>TMANE SELECT
NC_000002.11:g.130930851C>A
NM_017951.4:c.462+1G>T

Nucleotide change:

IVS5DS, G-T, +1

Links:

OMIM: 610457.0003; dbSNP: rs780446128

NCBI 1000 Genomes Browser:

rs780446128

Molecular consequence:

NM_001171083.2:c.244-383G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_017751.4:c.462+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_017951.5:c.345+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
Identifiers:: MONDO: MONDO:0032838; MedGen: C5231431; OMIM: 618622

Recent activity

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ead/Ea22-like family protein [Escherichia coli]
ead/Ea22-like family protein [Escherichia coli]
gi|2776372173|ref|WP_367745156.1|

Protein
alkaline phosphatase [Escherichia coli]
alkaline phosphatase [Escherichia coli]
gi|2776426753|ref|WP_367775631.1|

Protein
DUF6731 family protein [Escherichia coli]
DUF6731 family protein [Escherichia coli]
gi|2776433443|ref|WP_367776533.1|

Protein
LOC124900337 [Homo sapiens]
LOC124900337 [Homo sapiens]
Gene ID:124900337

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000996027	OMIM	no assertion criteria provided	Pathogenic (Oct 16, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002020770	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004041543	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000996027

OMIM

no assertion criteria provided

Pathogenic
(Oct 16, 2019)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002020770

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004041543

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 10, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Magini P, Smits DJ, Vandervore L, Schot R, Columbaro M, Kasteleijn E, van der Ent M, Palombo F, Lequin MH, Dremmen M, de Wit MCY, Severino M, Divizia MT, Striano P, Ordonez-Herrera N, Alhashem A, Al Fares A, Al Ghamdi M, Rolfs A, Bauer P, Demmers J, Verheijen FW, et al.

Am J Hum Genet. 2019 Oct 3;105(4):689-705. doi: 10.1016/j.ajhg.2019.08.006. Epub 2019 Sep 5.

PubMed [citation]

PMID:: 31495489
PMCID:: PMC6817560

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000996027.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 sibs, born of unrelated Caucasian parents (family 3) with neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA; 618622), Magini et al. (2019) identified compound heterozygous mutations in the SMPD4 gene: a G-to-T transversion (c.462+1G-T, NM_017951.4) in intron 5, predicted to result in a splicing defect, and a c.199C-T transition in exon 3, resulting in a gln67-to-ter (Q67X; 610457.0004) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The splice site mutation was found at a low frequency (0.00041%) in the gnomAD database, whereas Q67X was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020770.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004041543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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