Genetic Variant ERP29:p.Leu24Ile (chr12-112013535-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006817.4(ERP29):c.70C>A(p.Leu24Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,612,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L24F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ERP29
NM_006817.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.423

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008004069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006817.4. 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
	ERP29	NM_006817.4	MANE Select	c.70C>A	p.Leu24Ile	missense	Exon 1 of 3	NP_006808.1	P30040-1
	ERP29	NM_001034025.2		c.70C>A	p.Leu24Ile	missense	Exon 1 of 2	NP_001029197.1	P30040-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERP29	ENST00000261735.4	TSL:1 MANE Select	c.70C>A	p.Leu24Ile	missense	Exon 1 of 3	ENSP00000261735.3	P30040-1
ERP29	ENST00000553161.1	TSL:1	n.107C>A		non_coding_transcript_exon	Exon 1 of 2
TMEM116	ENST00000716727.1		c.-42G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000520597.1	A0ABB0MV05

Frequencies

GnomAD3 genomes

AF:

0.0000722

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00211

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000144

AC:

AN:

249344

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00194

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460582

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.000812

AC:

AN:

39402

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111502

Other (OTH)

AF:

0.0000497

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.0000939

AC XY:

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41594

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00212

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.69

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

0.42

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.010

REVEL

Benign

0.070

Sift

Benign

0.89

Sift4G

Benign

0.38

Polyphen

0.084

Vest4

0.18

MutPred

0.39

Gain of helix (P = 0.0496)

MVP

0.14

MPC

0.22

ClinPred

0.061

GERP RS

3.8

PromoterAI

-0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.091

gMVP

0.33

Mutation Taster

=94/6

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over