18-2656077-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_015295.3(SMCHD1):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMCHD1 NM_015295.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.188

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.2T>G	p.Met1?	start_lost	1/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.2T>G	p.Met1?	start_lost	1/48	5	NM_015295.3	P2
SMCHD1	ENST00000688342.1	c.2T>G	p.Met1?	start_lost	1/47			A2
SMCHD1	ENST00000684915.1	n.159T>G		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 11, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.072	B
Vest4		0.59
MutPred		0.79		Gain of methylation at M1 (P = 0.0029);
MVP		0.44
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.97
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555622203; hg19: chr18-2656076;