rs869320626

Positions:

• chr1-19220834-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000477853.6(EMC1):​c.2602G>A​(p.Gly868Arg) 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 (★). Synonymous variant affecting the same amino acid position (i.e. G868G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EMC1 ENST00000477853.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.23

Genes affected

EMC1 (HGNC:28957): (ER membrane protein complex subunit 1) This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]

EMC1-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC1	NM_015047.3	c.2602G>A	p.Gly868Arg	missense_variant	21/23	ENST00000477853.6	NP_055862.1
EMC1-AS1	NR_135114.1	n.174+10275C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6	c.2602G>A	p.Gly868Arg	missense_variant	21/23	1	NM_015047.3	ENSP00000420608	P4
EMC1-AS1	ENST00000437898.3	n.212+10275C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebellar atrophy, visual impairment, and psychomotor retardation; Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 29, 2016

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not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.78		Gain of solvent accessibility (P = 0.0055);.;.;
MVP		0.69
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -24
DS_AL_spliceai		0.28		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320626; hg19: chr1-19547328; COSMIC: COSV105931571;