15-98969440-G-C

Position:

• chr15-98969440-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001167902.2(PGPEP1L):​c.194C>G​(p.Ser65Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PGPEP1L NM_001167902.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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]

SYNM-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a active_site (size 0) in uniprot entity PGPIL_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGPEP1L	NM_001167902.2	c.194C>G	p.Ser65Cys	missense_variant	4/5	ENST00000535714.2	NP_001161374.1
PGPEP1L	NM_001102612.2	c.356C>G	p.Ser119Cys	missense_variant	4/5		NP_001096082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGPEP1L	ENST00000535714.2	c.194C>G	p.Ser65Cys	missense_variant	4/5	2	NM_001167902.2	ENSP00000437560.1
PGPEP1L	ENST00000378919.6	c.356C>G	p.Ser119Cys	missense_variant	4/5	1		ENSP00000368199.6
PGPEP1L	ENST00000637120.2	c.422C>G	p.Ser141Cys	missense_variant	4/5	5		ENSP00000490927.2
SYNM-AS1	ENST00000559468.1	n.267-3370C>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2024

The c.356C>G (p.S119C) alteration is located in exon 4 (coding exon 3) of the PGPEP1L gene. This alteration results from a C to G substitution at nucleotide position 356, causing the serine (S) at amino acid position 119 to be replaced by a cysteine (C). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.79
MutPred		0.84		.;Loss of catalytic residue at S119 (P = 0.0225);.;
MVP		0.51
MPC		0.14
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99512669;