chr18-2667017-G-A

Position:

• chr18-2667017-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 6.37

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_015295.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMCHD1. . Gene score misZ 3.6318 (greater than the threshold 3.09). Trascript score misZ 3.965 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.410G>A	p.Gly137Glu	missense_variant	3/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.410G>A	p.Gly137Glu	missense_variant	3/48	5	NM_015295.3	P2
SMCHD1	ENST00000688342.1	c.410G>A	p.Gly137Glu	missense_variant	3/47			A2
SMCHD1	ENST00000684915.1	n.567G>A		non_coding_transcript_exon_variant	3/14

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

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2012	- -
Pathogenic, no assertion criteria provided	research	MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital	-	- -

Facioscapulohumeral muscular dystrophy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2012

- -

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
MutationTaster	Benign	0.99	D;D
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

Other links and lift over

dbSNP: rs1057519644; hg19: chr18-2667016;