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NM_005359.6(SMAD4):c.787+2T>C AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 13, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002409459.1

Allele description [Variation Report for NM_005359.6(SMAD4):c.787+2T>C]

NM_005359.6(SMAD4):c.787+2T>C

Gene:
SMAD4:SMAD family member 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q21.2
Genomic location:
Preferred name:
NM_005359.6(SMAD4):c.787+2T>C
HGVS:
  • NC_000018.10:g.51058246T>C
  • NG_013013.2:g.95207T>C
  • NM_001407041.1:c.787+2T>C
  • NM_001407042.1:c.787+2T>C
  • NM_001407043.1:c.787+2T>C
  • NM_005359.6:c.787+2T>CMANE SELECT
  • LRG_318t1:c.787+2T>C
  • LRG_318:g.95207T>C
  • NC_000018.9:g.48584616T>C
  • NM_005359.5:c.787+2T>C
Links:
dbSNP: rs1909895611
NCBI 1000 Genomes Browser:
rs1909895611
Molecular consequence:
  • NM_001407041.1:c.787+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407042.1:c.787+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001407043.1:c.787+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_005359.6:c.787+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:
Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:
MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086
Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002680853Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Likely pathogenic
(Jan 13, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From Ambry Genetics, SCV002680853.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.787+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 5 in the SMAD4 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of forty amino acids that make up coding exon 5. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function based on an internal structural analysis indicating involvement in DNA binding and protein-protein interactions (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Feb 20, 2024