rs1135402739

Positions:

• chr18-2667022-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_015295.3(SMCHD1):​c.415A>C​(p.Asn139His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 7.07

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_015295.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMCHD1. . Gene score misZ 3.6318 (greater than the threshold 3.09). Trascript score misZ 3.965 (greater than threshold 3.09). GenCC has associacion of gene with facioscapulohumeral muscular dystrophy, arhinia, choanal atresia, and microphthalmia, hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome.
• PP5: Variant 18-2667022-A-C is Pathogenic according to our data. Variant chr18-2667022-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 431463.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-2667022-A-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3314355). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.415A>C	p.Asn139His	missense_variant	3/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.415A>C	p.Asn139His	missense_variant	3/48	5	NM_015295.3	P2
SMCHD1	ENST00000688342.1	c.415A>C	p.Asn139His	missense_variant	3/47			A2
SMCHD1	ENST00000684915.1	n.572A>C		non_coding_transcript_exon_variant	3/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	Benign	0.26
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.25		Gain of disorder (P = 0.0734);
MVP		0.24
MPC		1.7
ClinPred		0.87	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs1135402739; hg19: chr18-2667021; COSMIC: COSV55253802;