rs1460743863
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_015295.3(SMCHD1):c.2660G>C(p.Gly887Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000627 in 1,593,762 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
SMCHD1
NM_015295.3 missense
NM_015295.3 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 7.04
Genes affected
SMCHD1 (HGNC:29090): (structural maintenance of chromosomes flexible hinge domain containing 1) This gene encodes a protein which contains a hinge region domain found in members of the SMC (structural maintenance of chromosomes) protein family. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SMCHD1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.745
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMCHD1 | NM_015295.3 | c.2660G>C | p.Gly887Ala | missense_variant | 21/48 | ENST00000320876.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMCHD1 | ENST00000320876.11 | c.2660G>C | p.Gly887Ala | missense_variant | 21/48 | 5 | NM_015295.3 | P2 | |
ENST00000583546.1 | n.371-33075C>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151988Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000624 AC: 9AN: 1441774Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2AN XY: 716122
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Facioscapulohumeral muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 14, 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 SMCHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 464164). This variant has not been reported in the literature in individuals affected with SMCHD1-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 887 of the SMCHD1 protein (p.Gly887Ala). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 03, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of sheet (P = 0.1208);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at