2-219374881-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012100.4(DNPEP):​c.1381G>A​(p.Val461Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

DNPEP
NM_012100.4 missense

Scores

1
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.77
Variant links:
Genes affected
DNPEP (HGNC:2981): (aspartyl aminopeptidase) The protein encoded by this gene is an aminopeptidase which prefers acidic amino acids, and specifically favors aspartic acid over glutamic acid. It is thought to be a cytosolic protein involved in general metabolism of intracellular proteins. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.231403).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNPEPNM_012100.4 linkc.1381G>A p.Val461Ile missense_variant Exon 14 of 15 ENST00000273075.9 NP_036232.2 Q9ULA0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNPEPENST00000273075.9 linkc.1381G>A p.Val461Ile missense_variant Exon 14 of 15 1 NM_012100.4 ENSP00000273075.4 Q9ULA0-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000401
AC:
10
AN:
249296
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135258
show subpopulations
Gnomad AFR exome
AF:
0.0000646
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:
0.0000465
Gnomad NFE exome
AF:
0.0000707
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000506
AC:
74
AN:
1461866
Hom.:
0
Cov.:
34
AF XY:
0.0000468
AC XY:
34
AN XY:
727224
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:
0.0000187
Gnomad4 NFE exome
AF:
0.0000621
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000198
Hom.:
0
Bravo
AF:
0.0000378
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000248
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 16, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1381G>A (p.V461I) alteration is located in exon 14 (coding exon 14) of the DNPEP gene. This alteration results from a G to A substitution at nucleotide position 1381, causing the valine (V) at amino acid position 461 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
0.12
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.013
.;.;T;T
Eigen
Benign
0.079
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.80
T;.;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.23
T;T;T;T
MetaSVM
Benign
-0.97
T
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.60
.;N;N;N
REVEL
Benign
0.12
Sift
Benign
0.40
.;T;T;T
Sift4G
Benign
0.53
.;T;T;T
Polyphen
0.14
.;.;.;B
Vest4
0.33, 0.35, 0.33
MVP
0.42
MPC
0.23
ClinPred
0.13
T
GERP RS
5.3
gMVP
0.61

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.

Other links and lift over

dbSNP: rs368993821; hg19: chr2-220239603; API