dbSNP rs10502304: SMCHD1:c.2913+92T>A (chr18-2728688-T-A) – ACMG Classification: Benign (-20 pts)

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.2913+92T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,322,634 control chromosomes in the GnomAD database, including 33,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3113 hom., cov: 32)

Exomes 𝑓: 0.22 ( 30149 hom. )

Consequence

SMCHD1
NM_015295.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0130

Publications

4 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 (BayesDel_noAF=-0.78).

BP6

Variant 18-2728688-T-A is Benign according to our data. Variant chr18-2728688-T-A is described in ClinVar as Benign. ClinVar VariationId is 1266007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.2913+92T>A		intron_variant	Intron 23 of 47	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11 link	c.2913+92T>A		intron_variant	Intron 23 of 47	5	NM_015295.3	ENSP00000326603.7		A6NHR9-1

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29465

AN:

151878

Hom.:

3105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.455

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.211

Gnomad EAS

AF:

0.0759

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.201

GnomAD4 exome

AF:

0.221

AC:

259259

AN:

1170638

Hom.:

30149

Cov.:

AF XY:

0.223

AC XY:

129588

AN XY:

581820

show subpopulations

African (AFR)

AF:

0.119

AC:

2913

AN:

24432

American (AMR)

AF:

0.332

AC:

8015

AN:

24124

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

4255

AN:

19598

East Asian (EAS)

AF:

0.0754

AC:

2594

AN:

34408

South Asian (SAS)

AF:

0.276

AC:

16980

AN:

61578

European-Finnish (FIN)

AF:

0.231

AC:

9536

AN:

41194

Middle Eastern (MID)

AF:

0.165

AC:

732

AN:

4430

European-Non Finnish (NFE)

AF:

0.223

AC:

203640

AN:

911556

Other (OTH)

AF:

0.215

AC:

10594

AN:

49318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

9269

18539

27808

37078

46347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6896

13792

20688

27584

34480

<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:

0.194

AC:

29486

AN:

151996

Hom.:

3113

Cov.:

AF XY:

0.196

AC XY:

14567

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.117

AC:

4863

AN:

41490

American (AMR)

AF:

0.257

AC:

3925

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

732

AN:

3470

East Asian (EAS)

AF:

0.0763

AC:

395

AN:

5178

South Asian (SAS)

AF:

0.270

AC:

1299

AN:

4820

European-Finnish (FIN)

AF:

0.234

AC:

2469

AN:

10552

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.220

AC:

14908

AN:

67902

Other (OTH)

AF:

0.202

AC:

428

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1171

2341

3512

4682

5853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.211

Hom.:

441

Bravo

AF:

0.193

Asia WGS

AF:

0.200

AC:

697

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.4

(source)

DANN

Benign

0.66

PhyloP100

-0.013

Mutation Taster

=100/0

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