15-98969549-G-T

Position:

• chr15-98969549-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001167902.2(PGPEP1L):​c.85C>A​(p.Pro29Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 8.19

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGPEP1L	NM_001167902.2	c.85C>A	p.Pro29Thr	missense_variant	4/5	ENST00000535714.2	NP_001161374.1
PGPEP1L	NM_001102612.2	c.247C>A	p.Pro83Thr	missense_variant	4/5		NP_001096082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGPEP1L	ENST00000535714.2	c.85C>A	p.Pro29Thr	missense_variant	4/5	2	NM_001167902.2	ENSP00000437560.1
PGPEP1L	ENST00000378919.6	c.247C>A	p.Pro83Thr	missense_variant	4/5	1		ENSP00000368199.6
PGPEP1L	ENST00000637120.2	c.313C>A	p.Pro105Thr	missense_variant	4/5	5		ENSP00000490927.2
SYNM-AS1	ENST00000559468.1	n.267-3479C>A		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

May 14, 2024

The c.247C>A (p.P83T) alteration is located in exon 4 (coding exon 3) of the PGPEP1L gene. This alteration results from a C to A substitution at nucleotide position 247, causing the proline (P) at amino acid position 83 to be replaced by a threonine (T). 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	0.54
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.7	D;D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.82
MutPred		0.83		.;Loss of loop (P = 0.2237);.;
MVP		0.27
MPC		0.32
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.45

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: rs2017459952; hg19: chr15-99512778;