18-2724932-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K879E) has been classified as Uncertain significance.

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

Publications

35 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:

ENSG00000266049 (HGNC:):

ENSG00000266049 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 260640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.2637A>T	p.Lys879Asn	missense_variant	Exon 21 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11 link	c.2637A>T	p.Lys879Asn	missense_variant	Exon 21 of 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

GnomAD2 exomes

AF:

0.340

AC:

77058

AN:

226952

AF XY:

0.341

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 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

African (AFR)

AF:

0.0647

AC:

2147

AN:

33194

American (AMR)

AF:

0.303

AC:

12867

AN:

42408

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

7510

AN:

25510

East Asian (EAS)

AF:

0.208

AC:

8165

AN:

39246

South Asian (SAS)

AF:

0.197

AC:

16266

AN:

82536

European-Finnish (FIN)

AF:

0.476

AC:

24670

AN:

51784

Middle Eastern (MID)

AF:

0.294

AC:

1672

AN:

5684

European-Non Finnish (NFE)

AF:

0.447

AC:

488715

AN:

1093400

Other (OTH)

AF:

0.363

AC:

21475

AN:

59100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

14589

29178

43766

58355

72944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14488

28976

43464

57952

72440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.319

AC:

48458

AN:

151962

Hom.:

9762

Cov.:

AF XY:

0.319

AC XY:

23659

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0836

AC:

3471

AN:

41542

American (AMR)

AF:

0.363

AC:

5543

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1095

AN:

3468

East Asian (EAS)

AF:

0.188

AC:

969

AN:

5168

South Asian (SAS)

AF:

0.188

AC:

907

AN:

4816

European-Finnish (FIN)

AF:

0.475

AC:

5017

AN:

10564

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.448

AC:

30422

AN:

67838

Other (OTH)

AF:

0.311

AC:

656

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1499

2998

4496

5995

7494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Facioscapulohumeral muscular dystrophy 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

1.0

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over