rs1135402738

Variant names:

• chr18-2666993-T-A
• rs1135402738
• NM_015295.3:c.386T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP5

The NM_015295.3(SMCHD1):​c.386T>A​(p.Met129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M129R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-2666993-T-G is described in Lovd as [Pathogenic].
• 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.
• PP5: Variant 18-2666993-T-A is Pathogenic according to our data. Variant chr18-2666993-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 431462.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-2666993-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.386T>A	p.Met129Lys	missense_variant	Exon 3 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.386T>A	p.Met129Lys	missense_variant	Exon 3 of 48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.386T>A	p.Met129Lys	missense_variant	Exon 3 of 47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.543T>A		non_coding_transcript_exon_variant	Exon 3 of 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

-

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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.94	P
Vest4		0.92
MutPred		0.67		Gain of solvent accessibility (P = 0.012);
MVP		0.22
MPC		1.9
ClinPred		0.80	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.90

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: rs1135402738; hg19: chr18-2666992;