rs964459864
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_003072.5(SMARCA4):c.4862G>A(p.Arg1621Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,550,918 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 Uncertain significance (★★).
Frequency
Consequence
NM_003072.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.4958G>A | p.Arg1653Gln | missense_variant | Exon 35 of 36 | ENST00000646693.2 | NP_001374212.1 | |
SMARCA4 | NM_003072.5 | c.4862G>A | p.Arg1621Gln | missense_variant | Exon 34 of 35 | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4958G>A | p.Arg1653Gln | missense_variant | Exon 35 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.4862G>A | p.Arg1621Gln | missense_variant | Exon 34 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.4868G>A | p.Arg1623Gln | missense_variant | Exon 34 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.4772G>A | p.Arg1591Gln | missense_variant | Exon 34 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.4772G>A | p.Arg1591Gln | missense_variant | Exon 33 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.4772G>A | p.Arg1591Gln | missense_variant | Exon 33 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.4769G>A | p.Arg1590Gln | missense_variant | Exon 34 of 35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.4283G>A | p.Arg1428Gln | missense_variant | Exon 31 of 32 | ENSP00000496004.1 | ||||
SMARCA4 | ENST00000644963.1 | c.3512G>A | p.Arg1171Gln | missense_variant | Exon 27 of 28 | ENSP00000495599.1 | ||||
SMARCA4 | ENST00000644065.1 | c.3494G>A | p.Arg1165Gln | missense_variant | Exon 26 of 27 | ENSP00000493615.1 | ||||
SMARCA4 | ENST00000642350.1 | c.3356G>A | p.Arg1119Gln | missense_variant | Exon 26 of 27 | ENSP00000495355.1 | ||||
SMARCA4 | ENST00000643857.1 | c.3122G>A | p.Arg1041Gln | missense_variant | Exon 24 of 25 | ENSP00000494159.1 | ||||
SMARCA4 | ENST00000538456.4 | c.926G>A | p.Arg309Gln | missense_variant | Exon 7 of 8 | 3 | ENSP00000495197.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152264Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000214 AC: 3AN: 1398654Hom.: 0 Cov.: 33 AF XY: 0.00000290 AC XY: 2AN XY: 689878
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74384
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: SMARCA4 c.4958G>A (p.Arg1653Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.4958G>A in individuals affected with Coffin-Siris Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 571088). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Intellectual disability, autosomal dominant 16 Uncertain:1
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Rhabdoid tumor predisposition syndrome 2 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1653 of the SMARCA4 protein (p.Arg1653Gln). 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 variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 571088). 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. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R1653Q variant (also known as c.4958G>A), located in coding exon 34 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4958. The arginine at codon 1653 is replaced by glutamine, an amino acid with highly 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. -
SMARCA4-related disorder Uncertain:1
The SMARCA4 c.4958G>A variant is predicted to result in the amino acid substitution p.Arg1653Gln. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/571088/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at