rs1057519643

Variant names:

• chr18-2667015-A-C
• rs1057519643
• NM_015295.3:c.408A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-2667015-A-C
• chr18-2667015-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_015295.3(SMCHD1):​c.408A>C​(p.Glu136Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E136E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.00
• Publications: 2 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015295.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-2667015-A-C is Pathogenic according to our data. Variant chr18-2667015-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375764.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.408A>C	p.Glu136Asp	missense_variant	Exon 3 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.408A>C	p.Glu136Asp	missense_variant	Exon 3 of 48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.408A>C	p.Glu136Asp	missense_variant	Exon 3 of 47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.565A>C		non_coding_transcript_exon_variant	Exon 3 of 14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:3

Feb 27, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 28, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.13 (damaging >=0.6, benign <0.4), 3Cnet: 0.16 (damaging >=0.6, benign <0.15), Splice AI: NA (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SMCHD1 related disorder (ClinVar ID: VCV000375764 /PMID: 28067909). However, the evidence of pathogenicity is insufficient at this time. A different missense change at the same codon (p.Glu136Gly) has been reported to be associated with SMCHD1 related disorder (PMID: 28067911). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Facioscapulohumeral muscular dystrophy 2 Pathogenic:1 Uncertain:1

Oct 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 136 of the SMCHD1 protein (p.Glu136Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SMCHD1-related conditions (PMID: 28067909). ClinVar contains an entry for this variant (Variation ID: 375764). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMCHD1 protein function. 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. -

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MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.24		Gain of sheet (P = 0.0266);
MVP		0.28
MPC		1.6
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.71
Mutation Taster		=58/42	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519643; hg19: chr18-2667014;