17-3669429-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031298.4(EMC6):c.283A>C(p.Thr95Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EMC6 NM_031298.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.57

Genes affected

EMC6 (HGNC:28430): (ER membrane protein complex subunit 6) Contributes to membrane insertase activity. Involved in autophagosome assembly; 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 and integral component of omegasome membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

P2RX5-TAX1BP3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMC6	NM_031298.4	c.283A>C	p.Thr95Pro	missense_variant	2/2	ENST00000248378.6
P2RX5-TAX1BP3	NR_037928.1	n.4723T>G		non_coding_transcript_exon_variant	12/15
EMC6	NM_001014764.3	c.283A>C	p.Thr95Pro	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMC6	ENST00000248378.6	c.283A>C	p.Thr95Pro	missense_variant	2/2	1	NM_031298.4	P1
EMC6	ENST00000397133.2	c.283A>C	p.Thr95Pro	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.283A>C (p.T95P) alteration is located in exon 2 (coding exon 1) of the EMC6 gene. This alteration results from a A to C substitution at nucleotide position 283, causing the threonine (T) at amino acid position 95 to be replaced by a proline (P). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.066	T;T
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.79		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.45
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-3572723;