rs879253819

Variant names:

• chr1-19235151-C-G
• rs879253819
• NM_015047.3:c.1411G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_015047.3(EMC1):​c.1411G>C​(p.Gly471Arg) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G471E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EMC1 NM_015047.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 7.36

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-19235150-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3376739.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757
• PP5: Variant 1-19235151-C-G is Pathogenic according to our data. Variant chr1-19235151-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 219102.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-19235151-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC1	NM_015047.3	c.1411G>C	p.Gly471Arg	missense_variant	Exon 13 of 23	ENST00000477853.6	NP_055862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6	c.1411G>C	p.Gly471Arg	missense_variant	Exon 13 of 23	1	NM_015047.3	ENSP00000420608.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant has been identified in an individual with developmental delay, cerebellar atrophy, and scoliosis. Please see PMID: 26942288 for additional details. -

not specified Uncertain:1

-

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

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.011	T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.074	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		1.0	D;P;P
Vest4		0.92
MutPred		0.39		Gain of helix (P = 0.0164);.;.;
MVP		0.54
MPC		1.1
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.38
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879253819; hg19: chr1-19561645;