Genetic Variant NM_015295.3:c.29G>T (chr18-2656104-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015295.3(SMCHD1):c.29G>T(p.Gly10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,276,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.760

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:

ENSG00000293256 (HGNC:):

ENSG00000293256 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0777463).

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.29G>T	p.Gly10Val	missense	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.29G>T	p.Gly10Val	missense	Exon 1 of 48	ENSP00000326603.7	A6NHR9-1
SMCHD1	ENST00000939310.1		c.29G>T	p.Gly10Val	missense	Exon 1 of 48	ENSP00000609369.1
SMCHD1	ENST00000688342.1		c.29G>T	p.Gly10Val	missense	Exon 1 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000157

AC:

AN:

1276166

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

626472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25576

American (AMR)

AF:

0.00

AC:

AN:

16884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18752

East Asian (EAS)

AF:

0.00

AC:

AN:

30482

South Asian (SAS)

AF:

0.00

AC:

AN:

60028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5062

European-Non Finnish (NFE)

AF:

0.00000196

AC:

AN:

1021658

Other (OTH)

AF:

0.00

AC:

AN:

51478

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Facioscapulohumeral muscular dystrophy 2 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.058

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.52

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.078

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.76

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.43

REVEL

Benign

0.047

Sift

Uncertain

0.020

Sift4G

Benign

0.091

Polyphen

0.0

Vest4

0.17

MutPred

0.38

Gain of sheet (P = 0.0266)

MVP

0.043

MPC

0.82

ClinPred

0.061

GERP RS

-1.2

PromoterAI

0.073

Neutral

(source)

Varity_R

0.062

gMVP

0.14

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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