11-61250009-C-A

Variant names:

• chr11-61250009-C-A
• rs576990857
• NM_014224.5:c.1012C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014224.5(PGA5):​c.1012C>A​(p.Leu338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PGA5 NM_014224.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.02

Genes affected

PGA5 (HGNC:8887): (pepsinogen A5) 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

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=0.17251983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGA5	NM_014224.5	c.1012C>A	p.Leu338Met	missense_variant	Exon 8 of 9	ENST00000312403.10	NP_055039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGA5	ENST00000312403.10	c.1012C>A	p.Leu338Met	missense_variant	Exon 8 of 9	1	NM_014224.5	ENSP00000309542.6
PGA5	ENST00000451616.6	c.550C>A	p.Leu184Met	missense_variant	Exon 3 of 4	2		ENSP00000408739.2
PGA5	ENST00000541528.1	c.232C>A	p.Leu78Met	missense_variant	Exon 2 of 3	2		ENSP00000441981.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457700 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724946

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1012C>A (p.L338M) alteration is located in exon 8 (coding exon 8) of the PGA5 gene. This alteration results from a C to A substitution at nucleotide position 1012, causing the leucine (L) at amino acid position 338 to be replaced by a methionine (M). 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	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.19	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.19	T;D;D
Sift4G	Benign	0.098	T;T;T
Vest4		0.16
MutPred		0.56		Gain of disorder (P = 0.09);.;.;
MVP		0.30
MPC		0.55
ClinPred		0.32	T
GERP RS		1.4
Varity_R		0.20
gMVP		0.28

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

Other links and lift over

dbSNP: rs576990857; hg19: chr11-61017481; COSMIC: COSV100409275; COSMIC: COSV100409275;