Genetic Variant EMC3:p.Met208Thr (chr3-9969753-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001394674.1(EMC3):c.623T>C(p.Met208Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EMC3
NM_001394674.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC3	NM_001394674.1 link	c.623T>C	p.Met208Thr	missense_variant	Exon 7 of 8	ENST00000245046.7	NP_001381603.1
EMC3	NM_018447.4 link	c.623T>C	p.Met208Thr	missense_variant	Exon 8 of 9		NP_060917.1	Q9P0I2-1
EMC3	XM_005265321.4 link	c.623T>C	p.Met208Thr	missense_variant	Exon 8 of 8		XP_005265378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC3	ENST00000245046.7 link	c.623T>C	p.Met208Thr	missense_variant	Exon 7 of 8	1	NM_001394674.1	ENSP00000245046.2		Q9P0I2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.623T>C (p.M208T) alteration is located in exon 7 (coding exon 7) of the EMC3 gene. This alteration results from a T to C substitution at nucleotide position 623, causing the methionine (M) at amino acid position 208 to be replaced by a threonine (T). 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

0.31

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.090

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Benign

0.0066

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.4

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.61

Sift

Benign

0.11

Sift4G

Benign

0.52

Polyphen

0.027

Vest4

0.69

MutPred

0.43

Gain of glycosylation at M208 (P = 0.0205);

MVP

0.51

MPC

0.81

ClinPred

0.91

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.74

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over