2-219382135-C-A

Variant summary

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

The NM_012100.4(DNPEP):​c.941G>T​(p.Gly314Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000938 in 1,609,586 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 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

DNPEP
NM_012100.4 missense

Scores

13
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64
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 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, 0.967

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNPEPNM_012100.4 linkc.941G>T p.Gly314Val missense_variant Exon 11 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.941G>T p.Gly314Val missense_variant Exon 11 of 15 1 NM_012100.4 ENSP00000273075.4 Q9ULA0-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000220
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000139
AC:
34
AN:
245172
Hom.:
0
AF XY:
0.000142
AC XY:
19
AN XY:
133336
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:
0.000293
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000913
AC:
133
AN:
1457336
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
78
AN XY:
725134
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:
0.000117
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.0000941
AC XY:
7
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000220
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000769
Hom.:
0
Bravo
AF:
0.0000982
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 17, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.941G>T (p.G314V) alteration is located in exon 11 (coding exon 11) of the DNPEP gene. This alteration results from a G to T substitution at nucleotide position 941, causing the glycine (G) at amino acid position 314 to be replaced by a valine (V). 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
0.93
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
.;.;D;D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Pathogenic
0.82
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-8.8
.;D;D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;.
Polyphen
1.0
.;.;.;D;.
Vest4
0.98, 0.97
MVP
0.74
MPC
0.78
ClinPred
0.99
D
GERP RS
5.3
gMVP
0.89

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: rs766615900; hg19: chr2-220246857; API