chr17-3669169-G-T

Variant names:

• chr17-3669169-G-T
• rs2049973575
• NM_031298.4:c.23G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031298.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC6	NM_031298.4	MANE Select	c.23G>T	p.Arg8Leu	missense	Exon 2 of 2	NP_112588.1	Q9BV81
	EMC6	NM_001014764.3		c.23G>T	p.Arg8Leu	missense	Exon 2 of 2	NP_001014764.1	Q9BV81
	P2RX5-TAX1BP3	NR_037928.1		n.4983C>A		non_coding_transcript_exon	Exon 12 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC6	ENST00000248378.6	TSL:1 MANE Select	c.23G>T	p.Arg8Leu	missense	Exon 2 of 2	ENSP00000248378.4	Q9BV81
	P2RX5-TAX1BP3	ENST00000550383.1	TSL:2	n.*3285C>A		non_coding_transcript_exon	Exon 12 of 15	ENSP00000455681.1
	P2RX5-TAX1BP3	ENST00000550383.1	TSL:2	n.*3285C>A		3_prime_UTR	Exon 12 of 15	ENSP00000455681.1

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

African (AFR) AF: 0.0000311 AC: 1 AN: 32140

American (AMR) AF: 0.00 AC: 0 AN: 36964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25050

East Asian (EAS) AF: 0.00 AC: 0 AN: 36820

South Asian (SAS) AF: 0.00 AC: 0 AN: 81152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078062

Other (OTH) AF: 0.00 AC: 0 AN: 57844

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.23
Sift	Uncertain	0.022	D
Sift4G	Benign	0.097	T
Polyphen		0.39	B
Vest4		0.81
MutPred		0.59		Loss of solvent accessibility (P = 3e-04)
MVP		0.35
MPC		1.4
ClinPred		0.91	D
GERP RS		5.3
PromoterAI		0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.88
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs2049973575; hg19: chr17-3572463;