chr19-10987767-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001387283.1(SMARCA4):c.961G>A(p.Ala321Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000063 in 1,587,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A321P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.961G>A | p.Ala321Thr | missense_variant | 6/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.961G>A | p.Ala321Thr | missense_variant | 6/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.961G>A | p.Ala321Thr | missense_variant | 6/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.961G>A | p.Ala321Thr | missense_variant | 6/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000133 AC: 2AN: 150594Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000143 AC: 3AN: 209320Hom.: 0 AF XY: 0.00000866 AC XY: 1AN XY: 115514
GnomAD4 exome AF: 0.00000557 AC: 8AN: 1437248Hom.: 0 Cov.: 34 AF XY: 0.00000560 AC XY: 4AN XY: 713938
GnomAD4 genome AF: 0.0000133 AC: 2AN: 150594Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73450
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 470471). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 321 of the SMARCA4 protein (p.Ala321Thr). - |
Intellectual disability, autosomal dominant 16 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2023 | The p.A321T variant (also known as c.961G>A), located in coding exon 5 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 961. The alanine at codon 321 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) 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, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 09, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at