18-2656086-C-T

Variant names:

• chr18-2656086-C-T
• rs759215545
• NM_015295.3:c.11C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015295.3(SMCHD1):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.148
• Publications: 1 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

ENSG00000293256 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047104537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.168C>T		non_coding_transcript_exon_variant	Exon 1 of 14
ENSG00000293256	ENST00000733457.1	n.-216G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.00e-7 AC: 1 AN: 1249738 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 610610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25196

American (AMR) AF: 0.00 AC: 0 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17866

East Asian (EAS) AF: 0.00 AC: 0 AN: 29824

South Asian (SAS) AF: 0.00 AC: 0 AN: 55276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 9.92e-7 AC: 1 AN: 1007628

Other (OTH) AF: 0.00 AC: 0 AN: 50318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Facioscapulohumeral muscular dystrophy 2 Uncertain:1

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the SMCHD1 protein (p.Ala4Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SMCHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1962406). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.15
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.067
Sift	Benign	0.27	T
Sift4G	Benign	0.29	T
Polyphen		0.55	P
Vest4		0.085
MutPred		0.23		Gain of sheet (P = 0.0477);
MVP		0.25
MPC		0.65
ClinPred		0.22	T
GERP RS		2.4
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.046
gMVP		0.37
Mutation Taster		=89/11	polymorphism

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: rs759215545; hg19: chr18-2656085;