chr19-11021885-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001387283.1(SMARCA4):c.2777A>G(p.Asn926Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N926N) has been classified as Likely benign.
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.2777A>G | p.Asn926Ser | missense_variant | 19/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.2777A>G | p.Asn926Ser | missense_variant | 19/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.2777A>G | p.Asn926Ser | missense_variant | 19/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.2777A>G | p.Asn926Ser | missense_variant | 19/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461460Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727038
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 16 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Molecular Medicine, Children’s Hospital of Fudan University | Apr 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 12, 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) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 470319). This missense change has been observed in individual(s) with clinical features of SMARCA4-related conditions (PMID: 34813034). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 926 of the SMARCA4 protein (p.Asn926Ser). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2019 | The p.N926S variant (also known as c.2777A>G), located in coding exon 18 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2777. The asparagine at codon 926 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at