Genetic Variant NM_015295.3:c.4104delC (chr18-2750443-AC-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_015295.3(SMCHD1):c.4104delC(p.Val1369PhefsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,334 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P1368P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.43

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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, G2P
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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-2750443-AC-A is Pathogenic according to our data. Variant chr18-2750443-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 532807.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015295.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	NM_015295.3	MANE Select	c.4104delC	p.Val1369PhefsTer14	frameshift	Exon 32 of 48	NP_056110.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.4104delC	p.Val1369PhefsTer14	frameshift	Exon 32 of 48	ENSP00000326603.7	A6NHR9-1
SMCHD1	ENST00000939310.1		c.4017delC	p.Val1340PhefsTer14	frameshift	Exon 32 of 48	ENSP00000609369.1
SMCHD1	ENST00000688342.1		c.4104delC	p.Val1369PhefsTer14	frameshift	Exon 32 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459334

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00

AC:

AN:

85976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110580

Other (OTH)

AF:

0.00

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Facioscapulohumeral muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.4

Mutation Taster

=1/199

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over