3-9969753-A-G

Variant names:

• chr3-9969753-A-G
• NM_001394674.1:c.623T>C

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

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	c.623T>C	p.Met208Thr	missense_variant	Exon 7 of 8	ENST00000245046.7	NP_001381603.1
EMC3	NM_018447.4	c.623T>C	p.Met208Thr	missense_variant	Exon 8 of 9		NP_060917.1
EMC3	XM_005265321.4	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	c.623T>C	p.Met208Thr	missense_variant	Exon 7 of 8	1	NM_001394674.1	ENSP00000245046.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

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.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0066	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Benign	0.11	T
Sift4G	Benign	0.52	T
Polyphen		0.027	B
Vest4		0.69
MutPred		0.43		Gain of glycosylation at M208 (P = 0.0205);
MVP		0.51
MPC		0.81
ClinPred		0.91	D
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.

Other links and lift over

hg19: chr3-10011437;