rs191487554
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2
The NM_015295.3(SMCHD1):āc.4255A>Gā(p.Thr1419Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,573,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_015295.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMCHD1 | NM_015295.3 | c.4255A>G | p.Thr1419Ala | missense_variant | 33/48 | ENST00000320876.11 | NP_056110.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000482 AC: 10AN: 207588Hom.: 0 AF XY: 0.0000438 AC XY: 5AN XY: 114192
GnomAD4 exome AF: 0.0000373 AC: 53AN: 1421380Hom.: 0 Cov.: 29 AF XY: 0.0000255 AC XY: 18AN XY: 707072
GnomAD4 genome AF: 0.000276 AC: 42AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74422
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 10, 2017 | - - |
Facioscapulohumeral muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 05, 2024 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1419 of the SMCHD1 protein (p.Thr1419Ala). This variant is present in population databases (rs191487554, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SMCHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532802). 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 SMCHD1 protein function with a negative predictive value of 80%. 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