19-11013113-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003072.5(SMARCA4):c.2438+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_003072.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 35 | ENST00000646693.2 | NP_001374212.1 | ||
SMARCA4 | NM_003072.5 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 34 | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 35 | NM_001387283.1 | ENSP00000495368.1 | ||||
SMARCA4 | ENST00000344626.10 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 34 | 1 | NM_003072.5 | ENSP00000343896.4 | |||
SMARCA4 | ENST00000643549.1 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 34 | ENSP00000493975.1 | |||||
SMARCA4 | ENST00000541122.6 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 17 of 34 | 5 | ENSP00000445036.2 | ||||
SMARCA4 | ENST00000643296.1 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 33 | ENSP00000496635.1 | |||||
SMARCA4 | ENST00000644737.1 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 16 of 33 | ENSP00000495548.1 | |||||
SMARCA4 | ENST00000589677.5 | c.2438+1G>T | splice_donor_variant, intron_variant | Intron 17 of 34 | 5 | ENSP00000464778.1 | ||||
SMARCA4 | ENST00000643995.1 | c.1850+1G>T | splice_donor_variant, intron_variant | Intron 13 of 31 | ENSP00000496004.1 | |||||
SMARCA4 | ENST00000644963.1 | c.1082+1G>T | splice_donor_variant, intron_variant | Intron 9 of 27 | ENSP00000495599.1 | |||||
SMARCA4 | ENST00000644065.1 | c.1163+1G>T | splice_donor_variant, intron_variant | Intron 9 of 26 | ENSP00000493615.1 | |||||
SMARCA4 | ENST00000642350.1 | c.923+1G>T | splice_donor_variant, intron_variant | Intron 8 of 26 | ENSP00000495355.1 | |||||
SMARCA4 | ENST00000643857.1 | c.791+1G>T | splice_donor_variant, intron_variant | Intron 7 of 24 | ENSP00000494159.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
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. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.