rs765850087
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_003072.5(SMARCA4):c.1765G>A(p.Ala589Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_003072.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.1765G>A | p.Ala589Thr | missense_variant | 11/36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.1765G>A | p.Ala589Thr | missense_variant | 11/35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.1765G>A | p.Ala589Thr | missense_variant | 11/35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.1765G>A | p.Ala589Thr | missense_variant | 12/35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.1765G>A | p.Ala589Thr | missense_variant | 11/34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.1765G>A | p.Ala589Thr | missense_variant | 11/34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.1765G>A | p.Ala589Thr | missense_variant | 12/35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.1177G>A | p.Ala393Thr | missense_variant | 8/32 | ENSP00000496004.1 | ||||
SMARCA4 | ENST00000644963.1 | c.409G>A | p.Ala137Thr | missense_variant | 4/28 | ENSP00000495599.1 | ||||
SMARCA4 | ENST00000643857.1 | c.118G>A | p.Ala40Thr | missense_variant | 2/25 | ENSP00000494159.1 | ||||
SMARCA4 | ENST00000644065.1 | c.490G>A | p.Ala164Thr | missense_variant, splice_region_variant | 4/27 | ENSP00000493615.1 | ||||
SMARCA4 | ENST00000642350.1 | c.250G>A | p.Ala84Thr | missense_variant, splice_region_variant | 3/27 | ENSP00000495355.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135918
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74384
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2023 | The p.A589T variant (also known as c.1765G>A), located in coding exon 10 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1765. The alanine at codon 589 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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. - |
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 589 of the SMARCA4 protein (p.Ala589Thr). This variant is present in population databases (rs765850087, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 567661). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at