rs1135402745

chr18-2700842-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_015295.3(SMCHD1):c.1571A>G(p.Asn524Ser) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.76

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMCHD1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 18-2700842-A-G is Pathogenic according to our data. Variant chr18-2700842-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 431470.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-2700842-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.1571A>G	p.Asn524Ser	missense_variant	12/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.1571A>G	p.Asn524Ser	missense_variant	12/48	5	NM_015295.3	P2
	ENST00000583546.1	n.371-8962T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Benign	0.87
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.45		Loss of stability (P = 0.0809);
MVP		0.57
MPC		1.5
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.47
gMVP		0.94

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: rs1135402745; hg19: chr18-2700840;