Genetic Variant NM_015047.3:c.1751C>A (chr1-19232655-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_015047.3(EMC1):c.1751C>A(p.Pro584His) 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. P584R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

EMC1
NM_015047.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.33

Publications

1 publications found

Variant links:

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 links:

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

EMC1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-19232655-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801455.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

PP5

Variant 1-19232655-G-T is Pathogenic according to our data. Variant chr1-19232655-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521479.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015047.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EMC1	NM_015047.3	MANE Select	c.1751C>A	p.Pro584His	missense	Exon 15 of 23	NP_055862.1
EMC1	NM_001375820.1		c.1760C>A	p.Pro587His	missense	Exon 16 of 24	NP_001362749.1
EMC1	NM_001375821.1		c.1757C>A	p.Pro586His	missense	Exon 16 of 24	NP_001362750.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EMC1	ENST00000477853.6	TSL:1 MANE Select	c.1751C>A	p.Pro584His	missense	Exon 15 of 23	ENSP00000420608.1
EMC1	ENST00000375199.7	TSL:1	c.1748C>A	p.Pro583His	missense	Exon 15 of 23	ENSP00000364345.3
EMC1	ENST00000486405.2	TSL:2	c.1760C>A	p.Pro587His	missense	Exon 16 of 24	ENSP00000419345.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Dec 28, 2016

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.6

PhyloP100

9.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.84

MutPred

0.38

Gain of sheet (P = 0.039)

MVP

0.72

MPC

1.1

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.64

gMVP

0.59

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over