11-61249955-A-C

Variant names:

• chr11-61249955-A-C
• rs1029581223
• NM_014224.5:c.958A>C

Variant summary

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

The NM_014224.5(PGA5):​c.958A>C​(p.Ile320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,608 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I320V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: PGA5 NM_014224.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.423

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=0.2078566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGA5	NM_014224.5	c.958A>C	p.Ile320Leu	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.958A>C	p.Ile320Leu	missense_variant	Exon 8 of 9	1	NM_014224.5	ENSP00000309542.6
PGA5	ENST00000451616.6	c.496A>C	p.Ile166Leu	missense_variant	Exon 3 of 4	2		ENSP00000408739.2
PGA5	ENST00000541528.1	c.178A>C	p.Ile60Leu	missense_variant	Exon 2 of 3	2		ENSP00000441981.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151608 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151608 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74062

Gnomad4 AFR AF: 0.0000244

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.958A>C (p.I320L) alteration is located in exon 8 (coding exon 8) of the PGA5 gene. This alteration results from a A to C substitution at nucleotide position 958, causing the isoleucine (I) at amino acid position 320 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.52	N;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.045	D;T;T
Sift4G	Benign	0.23	T;T;T
Vest4		0.25
MutPred		0.63		Loss of catalytic residue at V321 (P = 0.1384);.;.;
MVP		0.21
MPC		0.51
ClinPred		0.37	T
GERP RS		2.4
Varity_R		0.094
gMVP		0.57

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: rs1029581223; hg19: chr11-61017427;