Submissions for variant NM_003072.5(SMARCA4):c.2438+1G>T

dbSNP: rs1555774786

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002458570	SCV002737231	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The c.2438+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 15 of the SMARCA4 gene. 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. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Loss-of-function variants in SMARCA4 are known to cause rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT); however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, this alteration is likely pathogenic for rhabdoid tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001733856	SCV001985002	not provided	not provided		no assertion provided	research