Variant 18-2656130-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_015295.3(SMCHD1):c.55G>C(p.Asp19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,337,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.388

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SMCHD1

BP4

Computational evidence support a benign effect (MetaRNN=0.07861325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3 linkuse as main transcript	c.55G>C	p.Asp19His	missense_variant	1/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11 linkuse as main transcript	c.55G>C	p.Asp19His	missense_variant	1/48	5	NM_015295.3	P2	A6NHR9-1
SMCHD1	ENST00000688342.1 linkuse as main transcript	c.55G>C	p.Asp19His	missense_variant	1/47			A2
SMCHD1	ENST00000684915.1 linkuse as main transcript	n.212G>C		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000688

AC:

AN:

145374

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000707

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1337710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

661666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000427

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.49e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Facioscapulohumeral muscular dystrophy 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 08, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 19 of the SMCHD1 protein (p.Asp19His). 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: 283671). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.054

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.52

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.25

REVEL

Benign

0.031

Sift

Benign

0.042

Sift4G

Pathogenic

0.0

Polyphen

0.070

Vest4

0.095

MutPred

0.23

Loss of sheet (P = 0.0817);

MVP

0.043

MPC

0.82

ClinPred

0.064

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.10

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over