Genetic Variant NM_001079807.4:c.88C>T (chr11-61204138-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001079807.4(PGA3):c.88C>T(p.Arg30Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 15)

Exomes 𝑓: 0.00015 ( 33 hom. )

Failed GnomAD Quality Control

Consequence

PGA3
NM_001079807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.13

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11128819).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079807.4. 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
	PGA3	NM_001079807.4	MANE Select	c.88C>T	p.Arg30Cys	missense	Exon 2 of 9	NP_001073275.1	P0DJD8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGA3	ENST00000325558.11	TSL:1 MANE Select	c.88C>T	p.Arg30Cys	missense	Exon 2 of 9	ENSP00000322192.6	P0DJD8
PGA3	ENST00000535551.1	TSL:3	n.832C>T		non_coding_transcript_exon	Exon 1 of 3
PGA3	ENST00000537954.5	TSL:2	n.138C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000104

AC:

AN:

114898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000607

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:

0.0000557

Gnomad OTH

AF:

0.00131

GnomAD2 exomes

AF:

0.000151

AC:

AN:

72888

AF XY:

0.000168

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.000276

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000182

Gnomad OTH exome

AF:

0.000939

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000154

AC:

192

AN:

1250686

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

627370

show subpopulations

African (AFR)

AF:

0.0000728

AC:

AN:

27486

American (AMR)

AF:

0.000423

AC:

AN:

42580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23102

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

81414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.000883

AC:

AN:

3398

European-Non Finnish (NFE)

AF:

0.000165

AC:

154

AN:

931034

Other (OTH)

AF:

0.000284

AC:

AN:

52734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000104

AC:

AN:

114956

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

55098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28132

American (AMR)

AF:

0.000606

AC:

AN:

11550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2778

East Asian (EAS)

AF:

0.00

AC:

AN:

5026

South Asian (SAS)

AF:

0.00

AC:

AN:

3702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.0000557

AC:

AN:

53884

Other (OTH)

AF:

0.00130

AC:

AN:

1542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00

Hom.:

ExAC

AF:

0.000272

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.4

PhyloP100

-2.1

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.15

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.15

MVP

0.043

MPC

3.0

ClinPred

0.26

GERP RS

-7.8

Varity_R

0.21

gMVP

0.16

Mutation Taster

=97/3

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