dbSNP rs747640131: PGA3:p.Thr61Asn (chr11-61204232-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001079807.4(PGA3):c.182C>A(p.Thr61Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. T61S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PGA3
NM_001079807.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07948238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGA3	NM_001079807.4 link	c.182C>A	p.Thr61Asn	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>A	p.Thr61Asn	missense_variant	Exon 2 of 9	1	NM_001079807.4	ENSP00000322192.6	P0DJD8
PGA3	ENST00000535551.1 link	n.926C>A		non_coding_transcript_exon_variant	Exon 1 of 3	3
PGA3	ENST00000537954.5 link	n.232C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
PGA3	ENST00000539649.1 link	n.232C>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000438

AC:

AN:

228494

Hom.:

AF XY:

0.00000809

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:

0.0000544

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

Data not reliable, filtered out with message: AS_VQSR

AF:

7.61e-7

AC:

AN:

1313332

Hom.:

Cov.:

AF XY:

0.00000153

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:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000884

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.92

DANN

Benign

0.14

DEOGEN2

Benign

0.0066

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.36

M_CAP

Benign

0.0084

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.30

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.18

REVEL

Benign

0.054

Sift

Benign

0.75

Sift4G

Benign

0.73

Vest4

0.12

MutPred

0.34

Loss of ubiquitination at K58 (P = 0.0787);

MVP

0.093

MPC

1.9

ClinPred

0.018

GERP RS

1.8

Varity_R

0.029

gMVP

0.080

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over