rs117771893

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015295.3(SMCHD1):c.1419A>G(p.Glu473Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,611,754 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 28 hom. )

Consequence

SMCHD1
NM_015295.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.855

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 18-2700615-A-G is Benign according to our data. Variant chr18-2700615-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.855 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00418 (636/152326) while in subpopulation NFE AF = 0.00495 (337/68024). AF 95% confidence interval is 0.00452. There are 2 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 636 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.1419A>G	p.Glu473Glu	synonymous_variant	Exon 11 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.1419A>G	p.Glu473Glu	synonymous_variant	Exon 11 of 48	5	NM_015295.3	ENSP00000326603.7		A6NHR9-1

Frequencies

GnomAD3 genomes

AF:

0.00419

AC:

637

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00495

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00401

AC:

982

AN:

245086

AF XY:

0.00418

show subpopulations

Gnomad AFR exome

AF:

0.000527

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.00181

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0142

Gnomad NFE exome

AF:

0.00429

Gnomad OTH exome

AF:

0.00502

GnomAD4 exome

AF:

0.00461

AC:

6729

AN:

1459428

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

3343

AN XY:

725920

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33442

American (AMR)

AF:

0.00234

AC:

104

AN:

44352

Ashkenazi Jewish (ASJ)

AF:

0.00196

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00227

AC:

195

AN:

86036

European-Finnish (FIN)

AF:

0.0118

AC:

631

AN:

53286

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00494

AC:

5482

AN:

1110628

Other (OTH)

AF:

0.00398

AC:

240

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00418

AC:

636

AN:

152326

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41568

American (AMR)

AF:

0.00268

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0170

AC:

181

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00495

AC:

337

AN:

68024

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00416

Hom.:

Bravo

AF:

0.00328

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMCHD1: BP4, BP7, BS2 -

not specified

Benign:2

Sep 07, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Facioscapulohumeral muscular dystrophy 2

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SMCHD1-related disorder

Benign:1

Apr 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.2

(source)

DANN

Benign

0.75

PhyloP100

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(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