19-11013113-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003072.5(SMARCA4):c.2438+1G>C 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>C | splice_donor_variant, intron_variant | Intron 16 of 35 | ENST00000646693.2 | NP_001374212.1 | ||
SMARCA4 | NM_003072.5 | c.2438+1G>C | 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>C | splice_donor_variant, intron_variant | Intron 16 of 35 | NM_001387283.1 | ENSP00000495368.1 | ||||
SMARCA4 | ENST00000344626.10 | c.2438+1G>C | splice_donor_variant, intron_variant | Intron 16 of 34 | 1 | NM_003072.5 | ENSP00000343896.4 | |||
SMARCA4 | ENST00000643549.1 | c.2438+1G>C | splice_donor_variant, intron_variant | Intron 16 of 34 | ENSP00000493975.1 | |||||
SMARCA4 | ENST00000541122.6 | c.2438+1G>C | splice_donor_variant, intron_variant | Intron 17 of 34 | 5 | ENSP00000445036.2 | ||||
SMARCA4 | ENST00000643296.1 | c.2438+1G>C | splice_donor_variant, intron_variant | Intron 16 of 33 | ENSP00000496635.1 | |||||
SMARCA4 | ENST00000644737.1 | c.2438+1G>C | splice_donor_variant, intron_variant | Intron 16 of 33 | ENSP00000495548.1 | |||||
SMARCA4 | ENST00000589677.5 | c.2438+1G>C | splice_donor_variant, intron_variant | Intron 17 of 34 | 5 | ENSP00000464778.1 | ||||
SMARCA4 | ENST00000643995.1 | c.1850+1G>C | splice_donor_variant, intron_variant | Intron 13 of 31 | ENSP00000496004.1 | |||||
SMARCA4 | ENST00000644963.1 | c.1082+1G>C | splice_donor_variant, intron_variant | Intron 9 of 27 | ENSP00000495599.1 | |||||
SMARCA4 | ENST00000644065.1 | c.1163+1G>C | splice_donor_variant, intron_variant | Intron 9 of 26 | ENSP00000493615.1 | |||||
SMARCA4 | ENST00000642350.1 | c.923+1G>C | splice_donor_variant, intron_variant | Intron 8 of 26 | ENSP00000495355.1 | |||||
SMARCA4 | ENST00000643857.1 | c.791+1G>C | 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>C intronic variant results from a G to C 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 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; however, direct evidence is insufficient at this time (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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at