chr12-112013472-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006817.4(ERP29):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ERP29
NM_006817.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Publications

0 publications found

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:

TMEM116 (HGNC:25084): (transmembrane protein 116) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM116 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERP29	NM_006817.4 link	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 3	ENST00000261735.4	NP_006808.1	P30040-1V9HW71
ERP29	NM_001034025.2 link	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 2		NP_001029197.1	P30040-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERP29	ENST00000261735.4 link	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 3	1	NM_006817.4	ENSP00000261735.3		P30040-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459200

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725886

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.00

AC:

AN:

86014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110718

Other (OTH)

AF:

0.00

AC:

AN:

60262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.066232), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7G>A (p.A3T) alteration is located in exon 1 (coding exon 1) of the ERP29 gene. This alteration results from a G to A substitution at nucleotide position 7, causing the alanine (A) at amino acid position 3 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

0.26

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L

PhyloP100

1.5

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.12

Sift

Benign

0.11

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.94

P;.

Vest4

0.25

MutPred

0.26

Gain of glycosylation at A3 (P = 0.0028);Gain of glycosylation at A3 (P = 0.0028);

MVP

0.26

MPC

0.19

ClinPred

0.75

GERP RS

3.8

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.61

Mutation Taster

=90/10

polymorphism

(source)

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

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chr12-112013472-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over