rs1057519644

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_015295.3(SMCHD1):​c.410G>A​(p.Gly137Glu) variant causes a missense change. 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 (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

SMCHD1
NM_015295.3 missense

Scores

6
10
3

Clinical Significance

Pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 6.37
Variant links:
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 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the SMCHD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.6318 (above the threshold of 3.09). Trascript score misZ: 3.965 (above the threshold of 3.09). GenCC associations: The gene is linked to facioscapulohumeral muscular dystrophy, arhinia, choanal atresia, and microphthalmia, hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.795
PP5
Variant 18-2667017-G-A is Pathogenic according to our data. Variant chr18-2667017-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 375765.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-2667017-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMCHD1NM_015295.3 linkc.410G>A p.Gly137Glu missense_variant Exon 3 of 48 ENST00000320876.11 NP_056110.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMCHD1ENST00000320876.11 linkc.410G>A p.Gly137Glu missense_variant Exon 3 of 48 5 NM_015295.3 ENSP00000326603.7 A6NHR9-1
SMCHD1ENST00000688342.1 linkc.410G>A p.Gly137Glu missense_variant Exon 3 of 47 ENSP00000508422.1 A0A8I5KRS9
SMCHD1ENST00000684915.1 linkn.567G>A non_coding_transcript_exon_variant Exon 3 of 14

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:2
Dec 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Facioscapulohumeral muscular dystrophy 2 Pathogenic:1
Dec 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.087
D
MetaRNN
Pathogenic
0.80
D
MetaSVM
Benign
-0.91
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-4.2
D
REVEL
Uncertain
0.35
Sift
Uncertain
0.011
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.80
MutPred
0.36
Gain of solvent accessibility (P = 0.024);
MVP
0.17
MPC
1.9
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.72
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057519644; hg19: chr18-2667016; API