18-2724932-A-T

Position:

chr18-2724932-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_015295.3(SMCHD1):c.2637A>T(p.Lys879Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,584,824 control chromosomes in the GnomAD database, including 135,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9762 hom., cov: 31)

Exomes 𝑓: 0.41 ( 125992 hom. )

Consequence

SMCHD1
NM_015295.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.03

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:

SMCHD1 (HGNC:):

SMCHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMCHD1. . Gene score misZ 3.6318 (greater than the threshold 3.09). Trascript score misZ 3.965 (greater than threshold 3.09). GenCC has associacion of gene with facioscapulohumeral muscular dystrophy, arhinia, choanal atresia, and microphthalmia, hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017078817).

BP6

Variant 18-2724932-A-T is Benign according to our data. Variant chr18-2724932-A-T is described in ClinVar as [Benign]. Clinvar id is 260640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2724932-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCHD1	NM_015295.3 linkuse as main transcript	c.2637A>T	p.Lys879Asn	missense_variant	21/48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11 linkuse as main transcript	c.2637A>T	p.Lys879Asn	missense_variant	21/48	5	NM_015295.3	ENSP00000326603.7		A6NHR9-1

Frequencies

GnomAD3 genomes

AF:

0.319

AC:

48467

AN:

151844

Hom.:

9766

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0838

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.475

Gnomad MID

AF:

0.290

Gnomad NFE

AF:

0.448

Gnomad OTH

AF:

0.312

GnomAD3 exomes

AF:

0.340

AC:

77058

AN:

226952

Hom.:

15027

AF XY:

0.341

AC XY:

41718

AN XY:

122364

show subpopulations

Gnomad AFR exome

AF:

0.0710

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.166

Gnomad SAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.476

Gnomad NFE exome

AF:

0.436

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.407

AC:

583487

AN:

1432862

Hom.:

125992

Cov.:

AF XY:

0.402

AC XY:

285855

AN XY:

711402

show subpopulations

Gnomad4 AFR exome

AF:

0.0647

Gnomad4 AMR exome

AF:

0.303

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.208

Gnomad4 SAS exome

AF:

0.197

Gnomad4 FIN exome

AF:

0.476

Gnomad4 NFE exome

AF:

0.447

Gnomad4 OTH exome

AF:

0.363

GnomAD4 genome

AF:

0.319

AC:

48458

AN:

151962

Hom.:

9762

Cov.:

AF XY:

0.319

AC XY:

23659

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.0836

Gnomad4 AMR

AF:

0.363

Gnomad4 ASJ

AF:

0.316

Gnomad4 EAS

AF:

0.188

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.475

Gnomad4 NFE

AF:

0.448

Gnomad4 OTH

AF:

0.311

Alfa

AF:

0.397

Hom.:

9480

Bravo

AF:

0.297

TwinsUK

AF:

0.444

AC:

1646

ALSPAC

AF:

0.442

AC:

1702

ESP6500AA

AF:

0.0826

AC:

299

ESP6500EA

AF:

0.438

AC:

3562

ExAC

AF:

0.330

AC:

39726

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Facioscapulohumeral muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.086

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.65

REVEL

Benign

0.091

Sift

Benign

0.34

Sift4G

Benign

0.22

Polyphen

0.0

Vest4

0.040

MutPred

0.11

Loss of methylation at K879 (P = 0.0135);

MPC

0.25

ClinPred

0.0029

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.069

gMVP

0.37

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