chr15-98968638-A-G

Variant names:

• chr15-98968638-A-G
• rs774084757
• NM_001167902.2:c.269T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001167902.2(PGPEP1L):​c.269T>C​(p.Leu90Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L90H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PGPEP1L NM_001167902.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.62
• Publications: 0 publications found

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:55421): (SYNM antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGPEP1L	NM_001167902.2	c.269T>C	p.Leu90Pro	missense_variant	Exon 5 of 5	ENST00000535714.2	NP_001161374.1
PGPEP1L	NM_001102612.2	c.431T>C	p.Leu144Pro	missense_variant	Exon 5 of 5		NP_001096082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGPEP1L	ENST00000535714.2	c.269T>C	p.Leu90Pro	missense_variant	Exon 5 of 5	2	NM_001167902.2	ENSP00000437560.1
PGPEP1L	ENST00000378919.6	c.431T>C	p.Leu144Pro	missense_variant	Exon 5 of 5	1		ENSP00000368199.6
PGPEP1L	ENST00000637120.2	c.497T>C	p.Leu166Pro	missense_variant	Exon 5 of 5	5		ENSP00000490927.2
SYNM-AS1	ENST00000559468.1	n.267-2568T>C		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446940 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 718088

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 42140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25816

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.00 AC: 0 AN: 83548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104682

Other (OTH) AF: 0.00 AC: 0 AN: 59958

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.6	.;M;.
PhyloP100		5.6
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.2	D;D;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.80
MutPred		0.81		.;Loss of stability (P = 0.0088);.;
MVP		0.41
MPC		0.37
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.74
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs774084757; hg19: chr15-99511867;