17-3669169-G-T

Variant names:

• chr17-3669169-G-T
• NM_031298.4:c.23G>T

Variant summary

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

The NM_031298.4(EMC6):​c.23G>T​(p.Arg8Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000645 in 1,394,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: EMC6 NM_031298.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

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:49191): (P2RX5-TAX1BP3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring P2RX5 (purinergic receptor P2X, ligand-gated ion channel, 5) and TAX1BP3 (Tax1 binding protein 3) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

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
EMC6	NM_031298.4	c.23G>T	p.Arg8Leu	missense_variant	Exon 2 of 2	ENST00000248378.6	NP_112588.1
EMC6	NM_001014764.3	c.23G>T	p.Arg8Leu	missense_variant	Exon 2 of 2		NP_001014764.1
P2RX5-TAX1BP3	NR_037928.1	n.4983C>A		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC6	ENST00000248378.6	c.23G>T	p.Arg8Leu	missense_variant	Exon 2 of 2	1	NM_031298.4	ENSP00000248378.4
P2RX5-TAX1BP3	ENST00000550383.1	n.*3285C>A		non_coding_transcript_exon_variant	Exon 12 of 15	2		ENSP00000455681.1
P2RX5-TAX1BP3	ENST00000550383.1	n.*3285C>A		3_prime_UTR_variant	Exon 12 of 15	2		ENSP00000455681.1
EMC6	ENST00000397133.2	c.23G>T	p.Arg8Leu	missense_variant	Exon 2 of 2	2		ENSP00000380322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000645 AC: 9 AN: 1394916 Hom.: 0 Cov.: 31 AF XY: 0.00000872 AC XY: 6 AN XY: 687836

Gnomad4 AFR exome AF: 0.0000311

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: 0.00000742

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23G>T (p.R8L) alteration is located in exon 2 (coding exon 1) of the EMC6 gene. This alteration results from a G to T substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.86	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.022	D;D
Sift4G	Benign	0.097	T;T
Polyphen		0.39	B;B
Vest4		0.81
MutPred		0.59		Loss of solvent accessibility (P = 3e-04);Loss of solvent accessibility (P = 3e-04);
MVP		0.35
MPC		1.4
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.88

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: chr17-3572463;