Genetic Variant ERP29:p.Leu17Pro (chr12-112013515-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_006817.4(ERP29):c.50T>C(p.Leu17Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,246 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: 6.8e-7 ( 0 hom. )

Consequence

ERP29
NM_006817.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

Variant links:

Genes affected

ERP29 (HGNC:13799): (endoplasmic reticulum protein 29) This gene encodes a protein which localizes to the lumen of the endoplasmic reticulum (ER). It is a member of the protein disulfide isomerase (PDI) protein family but lacks an active thioredoxin motif, suggesting that this protein does not function as a disulfide isomerase. The canonical protein dimerizes and is thought to play a role in the processing of secretory proteins within the ER. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

ERP29 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
ERP29	NM_006817.4 link	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 3	ENST00000261735.4	NP_006808.1	P30040-1V9HW71
ERP29	NM_001034025.2 link	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 2		NP_001029197.1	P30040-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERP29	ENST00000261735.4 link	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 3	1	NM_006817.4	ENSP00000261735.3	P30040-1
ERP29	ENST00000553161.1 link	n.87T>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
ERP29	ENST00000552052.1 link	c.34T>C	p.Phe12Leu	missense_variant	Exon 1 of 2	3		ENSP00000447472.1	F8W1G0
ERP29	ENST00000455836.1 link	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 2	2		ENSP00000412083.1	P30040-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249084

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726462

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50T>C (p.L17P) alteration is located in exon 1 (coding exon 1) of the ERP29 gene. This alteration results from a T to C substitution at nucleotide position 50, causing the leucine (L) at amino acid position 17 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

Benign

0.12

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;D

REVEL

Benign

0.27

Sift

Benign

0.075

T;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.80

P;.

Vest4

0.65

MutPred

0.69

Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);

MVP

0.39

MPC

0.50

ClinPred

0.41

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Varity_R

0.77

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over