chr19-45693413-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017659.4(QPCTL):​c.208G>A​(p.Val70Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

QPCTL
NM_017659.4 missense, splice_region

Scores

19
Splicing: ADA: 0.09992
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0160
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05468616).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
QPCTLNM_017659.4 linkuse as main transcriptc.208G>A p.Val70Ile missense_variant, splice_region_variant 2/7 ENST00000012049.10 NP_060129.2 Q9NXS2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
QPCTLENST00000012049.10 linkuse as main transcriptc.208G>A p.Val70Ile missense_variant, splice_region_variant 2/72 NM_017659.4 ENSP00000012049.4 Q9NXS2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1457750
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
724970
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000450
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 submitterclinical testingAmbry GeneticsJan 19, 2022The c.208G>A (p.V70I) alteration is located in exon 2 (coding exon 2) of the QPCTL gene. This alteration results from a G to A substitution at nucleotide position 208, causing the valine (V) at amino acid position 70 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
Benign
0.085
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
9.6
DANN
Benign
0.96
DEOGEN2
Benign
0.0074
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.080
N
LIST_S2
Benign
0.58
T;T
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.055
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.39
N;N
REVEL
Benign
0.016
Sift
Benign
0.38
T;T
Sift4G
Benign
0.39
T;T
Polyphen
0.0050
B;.
Vest4
0.23
MutPred
0.21
Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP
0.23
MPC
0.25
ClinPred
0.032
T
GERP RS
-1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.068
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.10
dbscSNV1_RF
Benign
0.29
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs1306431024; hg19: chr19-46196671; API