Genetic Variant NM_001079808.6:c.1057C>G (chr11-61231421-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001079808.6(PGA4):c.1057C>G(p.Leu353Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 5)

Exomes 𝑓: 0.0038 ( 16 hom. )

Failed GnomAD Quality Control

Consequence

PGA4
NM_001079808.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.23

Variant links:

Genes affected

PGA4 (HGNC:8886): (pepsinogen A4) This gene encodes a protein precursor of the digestive enzyme pepsin, a member of the peptidase A1 family of endopeptidases. The encoded precursor is secreted by gastric chief cells and undergoes autocatalytic cleavage in acidic conditions to form the active enzyme, which functions in the digestion of dietary proteins. This gene is found in a cluster of related genes on chromosome 11, each of which encodes one of multiple pepsinogens. Pepsinogen levels in serum may serve as a biomarker for atrophic gastritis and gastric cancer. [provided by RefSeq, Jul 2015]

PGA4 links:

ENSG00000256220 (HGNC:):

ENSG00000256220 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069322586).

BP6

Variant 11-61231421-C-G is Benign according to our data. Variant chr11-61231421-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2214254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGA4	NM_001079808.6 link	c.1057C>G	p.Leu353Val	missense_variant	Exon 9 of 9	ENST00000378149.9	NP_001073276.1	P0DJD7A0A1S5UZ02B7Z719

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGA4	ENST00000378149.9 link	c.1057C>G	p.Leu353Val	missense_variant	Exon 9 of 9	1	NM_001079808.6	ENSP00000367391.3		P0DJD7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

117

AN:

31714

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00783

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00309

Gnomad ASJ

AF:

0.00121

Gnomad EAS

AF:

0.000455

Gnomad SAS

AF:

0.00240

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00758

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.0114

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00382

AC:

1288

AN:

337266

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

657

AN XY:

176980

show subpopulations

Gnomad4 AFR exome

AF:

0.0185

Gnomad4 AMR exome

AF:

0.00475

Gnomad4 ASJ exome

AF:

0.00346

Gnomad4 EAS exome

AF:

0.000506

Gnomad4 SAS exome

AF:

0.00259

Gnomad4 FIN exome

AF:

0.00190

Gnomad4 NFE exome

AF:

0.00368

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00369

AC:

117

AN:

31750

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

AN XY:

14500

show subpopulations

Gnomad4 AFR

AF:

0.00779

Gnomad4 AMR

AF:

0.00308

Gnomad4 ASJ

AF:

0.00121

Gnomad4 EAS

AF:

0.000457

Gnomad4 SAS

AF:

0.00242

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.0112

Alfa

AF:

0.000687

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 12, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0010

DANN

Benign

0.48

DEOGEN2

Benign

0.062

T;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.0057

T;.;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.30

N;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.12

N;N;N

REVEL

Benign

0.040

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.59

T;T;T

Vest4

0.042

MutPred

0.14

Gain of sheet (P = 0.1945);.;.;

MVP

0.014

ClinPred

0.0094

GERP RS

-3.2

Varity_R

0.090

gMVP

0.063

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