chr19-18357503-G-T

Variant names:

• chr19-18357503-G-T
• NM_017712.4:c.325G>T
• PGPEP1 p.Val109Leu

Variant summary

Our verdict is

Uncertain significance

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017712.4(PGPEP1):​c.325G>T​(p.Val109Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V109M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGPEP1 NM_017712.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 0 publications found

Genes affected

PGPEP1 (HGNC:13568): (pyroglutamyl-peptidase I) The gene encodes a cysteine protease and member of the peptidase C15 family of proteins. The encoded protein cleaves amino terminal pyroglutamate residues from protein substrates including thyrotropin-releasing hormone and other neuropeptides. Expression of this gene may be downregulated in colorectal cancer, while activity of the encoded protein may be negatively correlated with cancer progression in colorectal cancer patients. Activity of the encoded protease may also be altered in other disease states including in liver cirrhosis, which is associated with reduced protease activity, and in necrozoospermia, which is associated with elevated protease activity. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.13).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017712.4. 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
	PGPEP1	NM_017712.4	MANE Select	c.325G>T	p.Val109Leu	missense	Exon 4 of 5	NP_060182.1	Q9NXJ5-1
	PGPEP1	NM_001329471.2		c.325G>T	p.Val109Leu	missense	Exon 4 of 5	NP_001316400.1
	PGPEP1	NM_001308366.2		c.325G>T	p.Val109Leu	missense	Exon 4 of 5	NP_001295295.1	S4R2Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGPEP1	ENST00000269919.11	TSL:1 MANE Select	c.325G>T	p.Val109Leu	missense	Exon 4 of 5	ENSP00000269919.3	Q9NXJ5-1
	PGPEP1	ENST00000596962.5	TSL:1	n.*176G>T		3_prime_UTR	Exon 5 of 6	ENSP00000470622.1	M0QX66
	PGPEP1	ENST00000600283.6	TSL:1	n.*176G>T		3_prime_UTR	Exon 5 of 6	ENSP00000468932.1	M0QX66

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.13
Sift	Benign	0.54	T
Sift4G	Benign	0.59	T
PromoterAI		0.010	Neutral
Varity_R		0.18
gMVP		0.38
Mutation Taster		=73/27	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-18468313;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline