rs281875184
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_003070.5(SMARCA2):c.3475C>G(p.Arg1159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1159L) has been classified as Pathogenic.
Frequency
Consequence
NM_003070.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA2 | NM_003070.5 | c.3475C>G | p.Arg1159Gly | missense_variant | 25/34 | ENST00000349721.8 | NP_003061.3 | |
SMARCA2 | NM_001289396.1 | c.3475C>G | p.Arg1159Gly | missense_variant | 25/34 | NP_001276325.1 | ||
SMARCA2 | NM_139045.4 | c.3475C>G | p.Arg1159Gly | missense_variant | 25/33 | NP_620614.2 | ||
SMARCA2 | NM_001289397.2 | c.3301C>G | p.Arg1101Gly | missense_variant | 25/33 | NP_001276326.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA2 | ENST00000349721.8 | c.3475C>G | p.Arg1159Gly | missense_variant | 25/34 | 5 | NM_003070.5 | ENSP00000265773.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Nicolaides-Baraitser syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 04, 2019 | Variant summary: SMARCA2 c.3475C>G (p.Arg1159Gly) results in a non-conservative amino acid change located in the Helicase, C-terminal domain (IPR001650) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250800 control chromosomes (gnomAD). c.3475C>G has been reported in the literature in individuals affected with Nicolaides-Baraitser syndrome (e.g. VanHoudt_2012, Sousa_2014), and was detected as a de-novo mutation in at least one of these patients (VanHoudt_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. In addition, p.R1159Q and p.R1159L have been reported in patients with Nicolaides-Baraitser syndrome (HGMD database). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 08, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant negative is a likely mechanism (PMID: 22366787). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed in four individuals with Nicolaides-Baraitser syndrome, one of which was confirmed de novo (ClinVar, PMID: 22366787, 25169058). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at