18-2667011-G-T

Position:

• chr18-2667011-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_015295.3(SMCHD1):​c.404G>T​(p.Ser135Ile) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S135C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.10

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]

SMCHD1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-2667010-A-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 18-2667011-G-T is Pathogenic according to our data. Variant chr18-2667011-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375768.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-2667011-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.404G>T	p.Ser135Ile	missense_variant	3/48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.404G>T	p.Ser135Ile	missense_variant	3/48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.404G>T	p.Ser135Ile	missense_variant	3/47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.561G>T		non_coding_transcript_exon_variant	3/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 27, 2017	- -
Pathogenic, no assertion criteria provided	research	MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32779700, 28067909) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.33		Loss of disorder (P = 0.005);
MVP		0.38
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.75
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: rs1057519646; hg19: chr18-2667010;