18-2706361-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015295.3(SMCHD1):c.1957-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,540,260 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 4 hom. )

Consequence

SMCHD1
NM_015295.3 splice_region, intron

Scores

Splicing: ADA: 0.0002092

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.637

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 18-2706361-C-T is Benign according to our data. Variant chr18-2706361-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 260635. Variant chr18-2706361-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 260635. Variant chr18-2706361-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 260635. Variant chr18-2706361-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 260635. Variant chr18-2706361-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 260635.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000519 (79/152174) while in subpopulation SAS AF = 0.00477 (23/4824). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.1957-3C>T		splice_region_variant, intron_variant	Intron 14 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.1957-3C>T		splice_region_variant, intron_variant	Intron 14 of 47	5	NM_015295.3	ENSP00000326603.7		A6NHR9-1

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000795

AC:

140

AN:

176008

AF XY:

0.000932

show subpopulations

Gnomad AFR exome

AF:

0.000190

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000765

Gnomad FIN exome

AF:

0.000110

Gnomad NFE exome

AF:

0.000579

Gnomad OTH exome

AF:

0.000434

GnomAD4 exome

AF:

0.000732

AC:

1016

AN:

1388086

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

565

AN XY:

685266

show subpopulations

African (AFR)

AF:

0.000286

AC:

AN:

31490

American (AMR)

AF:

0.000370

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.0000408

AC:

AN:

24520

East Asian (EAS)

AF:

0.00

AC:

AN:

37266

South Asian (SAS)

AF:

0.00424

AC:

316

AN:

74574

European-Finnish (FIN)

AF:

0.0000995

AC:

AN:

50244

Middle Eastern (MID)

AF:

0.00248

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.000581

AC:

623

AN:

1071662

Other (OTH)

AF:

0.000608

AC:

AN:

57520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000519

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41524

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00477

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000677

AC:

AN:

67996

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000413

Hom.:

Bravo

AF:

0.000340

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMCHD1: BP4, BS1, BS2 -

Apr 18, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 17, 2023

Revvity Omics, Revvity

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Facioscapulohumeral muscular dystrophy 2

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.51

CADD

Benign

(source)

DANN

Benign

0.41

PhyloP100

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.030

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