Variant 19-45695494-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_017659.4(QPCTL):c.409T>A(p.Phe137Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

QPCTL
NM_017659.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Variant links:

Genes affected

QPCTL (HGNC:25952): (glutaminyl-peptide cyclotransferase like) Enables glutaminyl-peptide cyclotransferase activity and zinc ion binding activity. Acts upstream of or within peptidyl-pyroglutamic acid biosynthetic process, using glutaminyl-peptide cyclotransferase. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

QPCTL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QPCTL	NM_017659.4 linkuse as main transcript	c.409T>A	p.Phe137Ile	missense_variant	3/7	ENST00000012049.10	NP_060129.2	Q9NXS2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QPCTL	ENST00000012049.10 linkuse as main transcript	c.409T>A	p.Phe137Ile	missense_variant	3/7	2	NM_017659.4	ENSP00000012049.4		Q9NXS2-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251336

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460908

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.409T>A (p.F137I) alteration is located in exon 3 (coding exon 3) of the QPCTL gene. This alteration results from a T to A substitution at nucleotide position 409, causing the phenylalanine (F) at amino acid position 137 to be replaced by an isoleucine (I). 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

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.85

Loss of catalytic residue at F137 (P = 0.0306);

MVP

0.72

MPC

1.2

ClinPred

0.99

GERP RS

5.0

Varity_R

0.93

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over