chr18-2694687-A-G

Variant names:

• chr18-2694687-A-G
• rs1057519639
• NM_015295.3:c.1034A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015295.3(SMCHD1):​c.1034A>G​(p.Gln345Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q345E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:3 U:1
• Conservation: PhyloP100: 8.29
• Publications: 3 publications found

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]

SMCHD1 Gene-Disease associations (from GenCC):

• arhinia, choanal atresia, and microphthalmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, ClinGen, Illumina
• facioscapulohumeral muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000266049 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4230785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.1034A>G	p.Gln345Arg	missense_variant	Exon 8 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.1034A>G	p.Gln345Arg	missense_variant	Exon 8 of 48	5	NM_015295.3	ENSP00000326603.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:2

-

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 27, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Anosmia Pathogenic:1

-

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Facioscapulohumeral muscular dystrophy 2 Uncertain:1

Jun 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change does not substantially affect SMCHD1 function (PMID: 31312724). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 375760). This missense change has been observed in individual(s) with autosomal dominant Bosma arhinia microphthalmia syndrome (PMID: 28067909). It has also been observed to segregate with disease in related individuals. This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 345 of the SMCHD1 protein (p.Gln345Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.22
Sift	Benign	0.075	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.46
MutPred		0.63		Gain of MoRF binding (P = 0.028);
MVP		0.31
MPC		1.7
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.70
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1057519639; hg19: chr18-2694685;