Genetic Variant PGA3:p.Thr61Ser (chr11-61204232-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001079807.4(PGA3):c.182C>G(p.Thr61Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,313,332 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000024 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

PGA3
NM_001079807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.825

Variant links:

Genes affected

PGA3 (HGNC:8885): (pepsinogen A3) 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]

PGA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06314272).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGA3	NM_001079807.4 link	c.182C>G	p.Thr61Ser	missense_variant	Exon 2 of 9	ENST00000325558.11	NP_001073275.1	P0DJD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PGA3	ENST00000325558.11 link	c.182C>G	p.Thr61Ser	missense_variant	Exon 2 of 9	1	NM_001079807.4	ENSP00000322192.6	P0DJD8
PGA3	ENST00000535551.1 link	n.926C>G		non_coding_transcript_exon_variant	Exon 1 of 3	3
PGA3	ENST00000537954.5 link	n.232C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
PGA3	ENST00000539649.1 link	n.232C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

133208

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000501

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000394

AC:

AN:

228494

Hom.:

AF XY:

0.0000647

AC XY:

AN XY:

123592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000696

Gnomad OTH exome

AF:

0.000359

GnomAD4 exome

AF:

0.0000244

AC:

AN:

1313332

Hom.:

Cov.:

AF XY:

0.0000229

AC XY:

AN XY:

654434

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:

0.0000293

Gnomad4 OTH exome

AF:

0.0000549

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000225

AC:

AN:

133208

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

65008

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000501

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000639

Hom.:

ExAC

AF:

0.0000265

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182C>G (p.T61S) alteration is located in exon 2 (coding exon 2) of the PGA3 gene. This alteration results from a C to G substitution at nucleotide position 182, causing the threonine (T) at amino acid position 61 to be replaced by a serine (S). 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

0.073

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.25

DANN

Benign

0.12

DEOGEN2

Benign

0.0049

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.27

M_CAP

Benign

0.0057

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.36

PrimateAI

Benign

0.37

PROVEAN

Benign

0.47

REVEL

Benign

0.060

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.076

MutPred

0.33

Loss of ubiquitination at K58 (P = 0.0709);

MVP

0.10

MPC

1.6

ClinPred

0.037

GERP RS

1.8

Varity_R

0.024

gMVP

0.072

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