Genetic Variant PGPEP1:c.*6216C>T (chr19-18369799-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017712.4(PGPEP1):c.*6216C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 151,968 control chromosomes in the GnomAD database, including 5,738 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 5737 hom., cov: 31)

Exomes 𝑓: 0.22 ( 1 hom. )

Consequence

PGPEP1
NM_017712.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.262

Publications

26 publications found

Variant links:

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]

PGPEP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGPEP1	NM_017712.4 link	c.*6216C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000269919.11	NP_060182.1	Q9NXJ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PGPEP1	ENST00000269919.11 link	c.*6216C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_017712.4	ENSP00000269919.3	Q9NXJ5-1
PGPEP1	ENST00000597663.2 link	c.231C>T	p.Pro77Pro	synonymous_variant	Exon 2 of 2	3		ENSP00000473226.2	M0R3H3
PGPEP1	ENST00000595552.2 link	c.*5C>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000471130.2	M0R0B6

Frequencies

GnomAD3 genomes

AF:

0.270

AC:

41031

AN:

151796

Hom.:

5718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.286

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.367

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.311

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.248

GnomAD2 exomes

AF:

0.245

AC:

600

AN:

2448

AF XY:

0.240

show subpopulations

Gnomad ASJ exome

AF:

0.300

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.0625

GnomAD4 exome

AF:

0.222

AC:

AN:

Hom.:

Cov.:

AF XY:

0.273

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.208

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.271

AC:

41096

AN:

151914

Hom.:

5737

Cov.:

AF XY:

0.275

AC XY:

20414

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.287

AC:

11868

AN:

41424

American (AMR)

AF:

0.352

AC:

5371

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

855

AN:

3468

East Asian (EAS)

AF:

0.367

AC:

1889

AN:

5142

South Asian (SAS)

AF:

0.199

AC:

959

AN:

4822

European-Finnish (FIN)

AF:

0.311

AC:

3277

AN:

10522

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.237

AC:

16123

AN:

67978

Other (OTH)

AF:

0.247

AC:

519

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1502

3004

4505

6007

7509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.241

Hom.:

9049

Bravo

AF:

0.278

Asia WGS

AF:

0.280

AC:

975

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.8

(source)

DANN

Benign

0.55

PhyloP100

0.26

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over