18-2688480-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_015295.3(SMCHD1):c.725C>G(p.Ala242Gly) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A242T) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SMCHD1
NM_015295.3 missense
NM_015295.3 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.13
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 Pathogenic. Variant got 10 ACMG points.
PM1
In a helix (size 8) in uniprot entity SMHD1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_015295.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr18-2688479-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant where missense usually causes diseases, SMCHD1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899
PP5
Variant 18-2688480-C-G is Pathogenic according to our data. Variant chr18-2688480-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 431466.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-2688480-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMCHD1 | NM_015295.3 | c.725C>G | p.Ala242Gly | missense_variant | 6/48 | ENST00000320876.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMCHD1 | ENST00000320876.11 | c.725C>G | p.Ala242Gly | missense_variant | 6/48 | 5 | NM_015295.3 | P2 | |
SMCHD1 | ENST00000688342.1 | c.725C>G | p.Ala242Gly | missense_variant | 6/47 | A2 | |||
SMCHD1 | ENST00000684915.1 | n.882C>G | non_coding_transcript_exon_variant | 6/14 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of sheet (P = 0.039);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at