Genetic Variant SMCHD1:p.Leu911Val (chr18-2726482-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015295.3(SMCHD1):c.2731T>G(p.Leu911Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L911I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMCHD1
NM_015295.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34157008).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	NM_015295.3	MANE Select	c.2731T>G	p.Leu911Val	missense	Exon 22 of 48	NP_056110.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.2731T>G	p.Leu911Val	missense	Exon 22 of 48	ENSP00000326603.7
SMCHD1	ENST00000688342.1		c.2731T>G	p.Leu911Val	missense	Exon 22 of 47	ENSP00000508422.1
SMCHD1	ENST00000577880.5	TSL:2	n.1144T>G		non_coding_transcript_exon	Exon 11 of 38	ENSP00000463049.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1356502

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669616

African (AFR)

AF:

0.00

AC:

AN:

30370

American (AMR)

AF:

0.00

AC:

AN:

34262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24518

East Asian (EAS)

AF:

0.00

AC:

AN:

34816

South Asian (SAS)

AF:

0.00

AC:

AN:

72256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050150

Other (OTH)

AF:

0.00

AC:

AN:

56238

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

M_CAP

Benign

0.050

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.3

PhyloP100

2.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.7

REVEL

Benign

0.16

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.45

MutPred

0.32

Gain of methylation at K912 (P = 0.0338)

MVP

0.16

MPC

0.41

ClinPred

0.89

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.46

Mutation Taster

=67/33

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over