11-61207571-G-A

Variant names:

• chr11-61207571-G-A
• rs1366830371
• NM_001079807.4:c.412G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001079807.4(PGA3):​c.412G>A​(p.Gly138Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000098 (0 hom., cov: 14)
  • Exomes 𝑓: 0.000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PGA3 NM_001079807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

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.412G>A	p.Gly138Ser	missense	Exon 4 of 9	NP_001073275.1	P0DJD8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGA3	ENST00000325558.11	TSL:1 MANE Select	c.412G>A	p.Gly138Ser	missense	Exon 4 of 9	ENSP00000322192.6	P0DJD8
	PGA3	ENST00000543505.5	TSL:3	c.193G>A	p.Gly65Ser	missense	Exon 2 of 6	ENSP00000443732.1	F5H842
	PGA3	ENST00000535551.1	TSL:3	n.1156G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00000981 AC: 1 AN: 101932 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000970

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000276 AC: 24 AN: 869714 Hom.: 0 Cov.: 13 AF XY: 0.0000400 AC XY: 18 AN XY: 449670

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000756 AC: 2 AN: 26448

American (AMR) AF: 0.00 AC: 0 AN: 41376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19982

East Asian (EAS) AF: 0.00 AC: 0 AN: 38848

South Asian (SAS) AF: 0.000237 AC: 18 AN: 75936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2604

European-Non Finnish (NFE) AF: 0.00000521 AC: 3 AN: 576366

Other (OTH) AF: 0.0000248 AC: 1 AN: 40386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000174798), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000981 AC: 1 AN: 101932 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 49574

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32052

American (AMR) AF: 0.0000970 AC: 1 AN: 10310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2220

East Asian (EAS) AF: 0.00 AC: 0 AN: 4570

South Asian (SAS) AF: 0.00 AC: 0 AN: 3386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 170

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 40836

Other (OTH) AF: 0.00 AC: 0 AN: 1194

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.46
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.6
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Vest4		0.67
MVP		0.74
MPC		2.7
ClinPred		0.95	D
GERP RS		2.7
Varity_R		0.33
gMVP		0.49
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs1366830371; hg19: chr11-60975043;