11-61204232-C-G

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

19

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]

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
PGA3NM_001079807.4 linkc.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 Appris UniProt
PGA3ENST00000325558.11 linkc.182C>G p.Thr61Ser missense_variant Exon 2 of 9 1 NM_001079807.4 ENSP00000322192.6 P0DJD8
PGA3ENST00000535551.1 linkn.926C>G non_coding_transcript_exon_variant Exon 1 of 3 3
PGA3ENST00000537954.5 linkn.232C>G non_coding_transcript_exon_variant Exon 2 of 2 2
PGA3ENST00000539649.1 linkn.232C>G non_coding_transcript_exon_variant Exon 2 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
3
AN:
133208
Hom.:
0
Cov.:
22
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:
9
AN:
228494
Hom.:
3
AF XY:
0.0000647
AC XY:
8
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:
32
AN:
1313332
Hom.:
7
Cov.:
30
AF XY:
0.0000229
AC XY:
15
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:
3
AN:
133208
Hom.:
0
Cov.:
22
AF XY:
0.0000308
AC XY:
2
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.:
0
ExAC
AF:
0.0000265
AC:
3

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
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
0.25
DANN
Benign
0.12
DEOGEN2
Benign
0.0049
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.27
T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.36
N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
0.47
N
REVEL
Benign
0.060
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Vest4
0.076
MutPred
0.33
Loss of ubiquitination at K58 (P = 0.0709);
MVP
0.10
MPC
1.6
ClinPred
0.037
T
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.

Other links and lift over

dbSNP: rs747640131; hg19: chr11-60971704; API