Genetic Variant SMCHD1:p.Glu18del (chr18-2656123-TGAG-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PM4_SupportingBS2

The NM_015295.3(SMCHD1):c.54_56delGGA(p.Glu18del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000608 in 1,479,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.781

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_015295.3. Strenght limited to Supporting due to length of the change: 1aa.

BS2

High AC in GnomAdExome4 at 8 AD gene.

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.54_56delGGA	p.Glu18del	disruptive_inframe_deletion	Exon 1 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.54_56delGGA	p.Glu18del	disruptive_inframe_deletion	Exon 1 of 48	ENSP00000326603.7	A6NHR9-1
SMCHD1	ENST00000939310.1		c.54_56delGGA	p.Glu18del	disruptive_inframe_deletion	Exon 1 of 48	ENSP00000609369.1
SMCHD1	ENST00000688342.1		c.54_56delGGA	p.Glu18del	disruptive_inframe_deletion	Exon 1 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000603

AC:

AN:

1327766

Hom.:

AF XY:

0.00000610

AC XY:

AN XY:

656158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26516

American (AMR)

AF:

0.00

AC:

AN:

22202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21044

East Asian (EAS)

AF:

0.00

AC:

AN:

31348

South Asian (SAS)

AF:

0.00

AC:

AN:

68680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5312

European-Non Finnish (NFE)

AF:

0.00000667

AC:

AN:

1048898

Other (OTH)

AF:

0.0000185

AC:

AN:

54176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.78

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over