dbSNP rs2715423: PGPEP1L:p.Ala88Val (chr15-98968644-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001167902.2(PGPEP1L):c.263C>T(p.Ala88Val) variant causes a missense change. The variant allele was found at a frequency of 0.255 in 1,595,292 control chromosomes in the GnomAD database, including 55,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. A88T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.21 ( 3927 hom., cov: 33)

Exomes 𝑓: 0.26 ( 51295 hom. )

Consequence

PGPEP1L
NM_001167902.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.25

Publications

26 publications found

Variant links:

Genes affected

PGPEP1L (HGNC:27080): (pyroglutamyl-peptidase I like) Predicted to enable pyroglutamyl-peptidase activity. Predicted to be involved in proteolysis. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PGPEP1L links:

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

SYNM-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.00658828).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGPEP1L	NM_001167902.2 link	c.263C>T	p.Ala88Val	missense_variant	Exon 5 of 5	ENST00000535714.2	NP_001161374.1	A6NFU8-2
PGPEP1L	NM_001102612.2 link	c.425C>T	p.Ala142Val	missense_variant	Exon 5 of 5		NP_001096082.2	A6NFU8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PGPEP1L	ENST00000535714.2 link	c.263C>T	p.Ala88Val	missense_variant	Exon 5 of 5	2	NM_001167902.2	ENSP00000437560.1	A6NFU8-2
PGPEP1L	ENST00000378919.6 link	c.425C>T	p.Ala142Val	missense_variant	Exon 5 of 5	1		ENSP00000368199.6	A6NFU8-1
PGPEP1L	ENST00000637120.2 link	c.491C>T	p.Ala164Val	missense_variant	Exon 5 of 5	5		ENSP00000490927.2	A0A1B0GWH3
SYNM-AS1	ENST00000559468.1 link	n.267-2574C>T		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.208

AC:

31610

AN:

152084

Hom.:

3925

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0907

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.212

Gnomad EAS

AF:

0.0669

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.280

Gnomad OTH

AF:

0.204

GnomAD2 exomes

AF:

0.228

AC:

49869

AN:

218726

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.0877

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.208

Gnomad EAS exome

AF:

0.0693

Gnomad FIN exome

AF:

0.309

Gnomad NFE exome

AF:

0.289

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.259

AC:

374451

AN:

1443090

Hom.:

51295

Cov.:

AF XY:

0.257

AC XY:

183887

AN XY:

715900

show subpopulations

African (AFR)

AF:

0.0857

AC:

2849

AN:

33248

American (AMR)

AF:

0.201

AC:

8322

AN:

41486

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

5377

AN:

25760

East Asian (EAS)

AF:

0.0527

AC:

2055

AN:

39014

South Asian (SAS)

AF:

0.144

AC:

11965

AN:

83228

European-Finnish (FIN)

AF:

0.307

AC:

16064

AN:

52284

Middle Eastern (MID)

AF:

0.196

AC:

1127

AN:

5742

European-Non Finnish (NFE)

AF:

0.284

AC:

312677

AN:

1102506

Other (OTH)

AF:

0.234

AC:

14015

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

15824

31648

47473

63297

79121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10148

20296

30444

40592

50740

<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:

0.208

AC:

31602

AN:

152202

Hom.:

3927

Cov.:

AF XY:

0.206

AC XY:

15323

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0904

AC:

3757

AN:

41546

American (AMR)

AF:

0.206

AC:

3147

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

736

AN:

3470

East Asian (EAS)

AF:

0.0663

AC:

344

AN:

5186

South Asian (SAS)

AF:

0.127

AC:

612

AN:

4820

European-Finnish (FIN)

AF:

0.303

AC:

3203

AN:

10578

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.280

AC:

19006

AN:

67998

Other (OTH)

AF:

0.202

AC:

426

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1262

2523

3785

5046

6308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.251

Hom.:

17809

Bravo

AF:

0.196

TwinsUK

AF:

0.287

AC:

1063

ALSPAC

AF:

0.293

AC:

1130

ESP6500AA

AF:

0.0927

AC:

370

ESP6500EA

AF:

0.273

AC:

2266

ExAC

AF:

0.211

AC:

25400

Asia WGS

AF:

0.134

AC:

467

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

.;T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.74

T;T;T

MetaRNN

Benign

0.0066

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

.;L;.

PhyloP100

5.3

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Benign

0.12

Sift

Uncertain

0.0090

D;D;.

Sift4G

Benign

0.19

T;T;.

Polyphen

0.16

.;B;.

Vest4

0.15

MPC

0.10

ClinPred

0.041

GERP RS

3.2

Varity_R

0.23

gMVP

0.33

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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