18-2656090-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015295.3(SMCHD1):c.15C>A(p.Asp5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,249,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D5D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.172

Publications

1 publications found

Variant links:

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

SMCHD1 links:

ENSG00000293256 (HGNC:):

ENSG00000293256 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.03888157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.15C>A	p.Asp5Glu	missense_variant	Exon 1 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMCHD1	ENST00000320876.11 link	c.15C>A	p.Asp5Glu	missense_variant	Exon 1 of 48	5	NM_015295.3	ENSP00000326603.7	A6NHR9-1
SMCHD1	ENST00000688342.1 link	c.15C>A	p.Asp5Glu	missense_variant	Exon 1 of 47			ENSP00000508422.1	A0A8I5KRS9
SMCHD1	ENST00000684915.1 link	n.172C>A		non_coding_transcript_exon_variant	Exon 1 of 14
ENSG00000293256	ENST00000733457.1 link	n.-220G>T		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

82516

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000160

AC:

AN:

1249600

Hom.:

Cov.:

AF XY:

0.00000164

AC XY:

AN XY:

610596

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25162

American (AMR)

AF:

0.0000674

AC:

AN:

14828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17832

East Asian (EAS)

AF:

0.0000336

AC:

AN:

29762

South Asian (SAS)

AF:

0.00

AC:

AN:

55522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4920

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1007670

Other (OTH)

AF:

0.00

AC:

AN:

50302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Facioscapulohumeral muscular dystrophy 2

Uncertain:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 5 of the SMCHD1 protein (p.Asp5Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 464163). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Benign

0.086

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.053

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.40

M_CAP

Benign

0.044

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

-0.17

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.21

REVEL

Benign

0.024

Sift

Benign

0.65

Sift4G

Benign

0.98

Polyphen

0.048

Vest4

0.027

MutPred

0.25

Gain of sheet (P = 0.1945);

MVP

0.12

MPC

0.61

ClinPred

0.040

GERP RS

1.8

PromoterAI

0.079

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.088

gMVP

0.099

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

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18-2656090-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over