rs1057519642

Positions:

• chr18-2697898-A-T

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.1199A>T​(p.Gln400Leu) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:4
• Conservation: PhyloP100: 8.46

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, 0.825
• PP5: Variant 18-2697898-A-T is Pathogenic according to our data. Variant chr18-2697898-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 375763.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-2697898-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.1199A>T	p.Gln400Leu	missense_variant	10/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.1199A>T	p.Gln400Leu	missense_variant	10/48	5	NM_015295.3	P2
	ENST00000583546.1	n.371-6018T>A		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:4

Revision: no assertion criteria provided

Submissions by phenotype

Arrhinia with choanal atresia and microphthalmia syndrome Pathogenic:2

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

Anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

research

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

-

- -

Short nose Pathogenic:1

Pathogenic, no assertion criteria provided

research

MGH Harvard Center for Reproductive Medicine, Massachusetts General Hospital

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.94
MutPred		0.40		Gain of helix (P = 0.062);
MVP		0.48
MPC		1.7
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.71

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: rs1057519642; hg19: chr18-2697896;