rs1556886034
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_006306.4(SMC1A):c.3197G>A(p.Arg1066His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1066C) has been classified as Pathogenic.
Frequency
Consequence
NM_006306.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC1A | NM_006306.4 | c.3197G>A | p.Arg1066His | missense_variant | 21/25 | ENST00000322213.9 | |
SMC1A | NM_001281463.1 | c.3131G>A | p.Arg1044His | missense_variant | 22/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC1A | ENST00000322213.9 | c.3197G>A | p.Arg1066His | missense_variant | 21/25 | 1 | NM_006306.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2017 | - - |
Congenital muscular hypertrophy-cerebral syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2017 | This sequence change replaces arginine with histidine at codon 1066 of the SMC1A protein (p.Arg1066His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been found to be de novo in an individual with clinical features consistent with SMC1A-related disorders (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg1066Cys) has been determined to be pathogenic (PMID: 25356970). This suggests that the arginine residue is critical for SMC1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at