rs1135402740

Variant names:

• chr18-2674018-T-G
• rs1135402740
• NM_015295.3:c.511T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_015295.3(SMCHD1):​c.511T>G​(p.Phe171Val) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.32

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMCHD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.6318 (above the threshold of 3.09). Trascript score misZ: 3.965 (above the threshold of 3.09). GenCC associations: The gene is linked to facioscapulohumeral muscular dystrophy, arhinia, choanal atresia, and microphthalmia, hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.511T>G	p.Phe171Val	missense_variant	Exon 5 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.511T>G	p.Phe171Val	missense_variant	Exon 5 of 48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.511T>G	p.Phe171Val	missense_variant	Exon 5 of 47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.668T>G		non_coding_transcript_exon_variant	Exon 5 of 14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:1 Uncertain:1

-

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 21, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PM1, PM2, PP3, PP3 -

Cryptorchidism;C0240701:Microphallus;C1854114:Short nose Pathogenic:1

-

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.043	D
Polyphen		0.94	P
Vest4		0.88
MutPred		0.64		Gain of sheet (P = 0.0149);
MVP		0.69
MPC		1.9
ClinPred		0.87	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.87

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: rs1135402740; hg19: chr18-2674017;