Genetic Variant EMC3:p.Asp41Asn (chr3-9986541-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001394674.1(EMC3):c.121G>A(p.Asp41Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

EMC3
NM_001394674.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.72

Variant links:

Genes affected

EMC3 (HGNC:23999): (ER membrane protein complex subunit 3) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

EMC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3471552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC3	NM_001394674.1 link	c.121G>A	p.Asp41Asn	missense_variant	Exon 1 of 8	ENST00000245046.7	NP_001381603.1
EMC3	NM_018447.4 link	c.121G>A	p.Asp41Asn	missense_variant	Exon 2 of 9		NP_060917.1	Q9P0I2-1
EMC3	XM_005265321.4 link	c.121G>A	p.Asp41Asn	missense_variant	Exon 2 of 8		XP_005265378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC3	ENST00000245046.7 link	c.121G>A	p.Asp41Asn	missense_variant	Exon 1 of 8	1	NM_001394674.1	ENSP00000245046.2		Q9P0I2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121G>A (p.D41N) alteration is located in exon 1 (coding exon 1) of the EMC3 gene. This alteration results from a G to A substitution at nucleotide position 121, causing the aspartic acid (D) at amino acid position 41 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

T;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.5

L;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.18

Sift

Benign

0.094

T;T;.

Sift4G

Benign

0.49

T;T;.

Polyphen

0.90

P;.;.

Vest4

0.61

MutPred

0.40

Loss of stability (P = 0.0636);Loss of stability (P = 0.0636);Loss of stability (P = 0.0636);

MVP

0.35

MPC

0.76

ClinPred

0.94

GERP RS

4.8

Varity_R

0.48

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over