Genetic Variant NM_139159.5:c.1990A>C (chr19-4685667-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_139159.5(DPP9):c.1990A>C(p.Lys664Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. K664E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPP9
NM_139159.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

Genes affected

DPP9 (HGNC:18648): (dipeptidyl peptidase 9) This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. The protein has been shown to have post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Although the activity of this protein is similar to that of dipeptidyl peptidase 4 (DPP4), it does not appear to be membrane bound. In general, dipeptidyl peptidases appear to be involved in the regulation of the activity of their substrates and have been linked to a variety of diseases including type 2 diabetes, obesity and cancer. Several transcript variants of this gene have been described but not fully characterized. [provided by RefSeq, Jul 2008]

DPP9 links:

DPP9-AS1 (HGNC:50706): (DPP9 antisense RNA 1)

DPP9-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33511597).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139159.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPP9	NM_139159.5	MANE Select	c.1990A>C	p.Lys664Gln	missense	Exon 17 of 22	NP_631898.3
DPP9	NM_001384611.1		c.1990A>C	p.Lys664Gln	missense	Exon 16 of 21	NP_001371540.1	Q86TI2-2
DPP9	NM_001384612.1		c.1990A>C	p.Lys664Gln	missense	Exon 18 of 23	NP_001371541.1	Q86TI2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPP9	ENST00000262960.14	TSL:1 MANE Select	c.1990A>C	p.Lys664Gln	missense	Exon 17 of 22	ENSP00000262960.8	Q86TI2-2
DPP9	ENST00000600621.6	TSL:4	c.1990A>C	p.Lys664Gln	missense	Exon 17 of 22	ENSP00000472549.2	Q86TI2-2
DPP9	ENST00000601130.6	TSL:4	c.1990A>C	p.Lys664Gln	missense	Exon 18 of 23	ENSP00000471629.2	Q86TI2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460412

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111508

Other (OTH)

AF:

0.00

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

0.067

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.022

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.3

PhyloP100

3.3

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

REVEL

Benign

0.095

Sift

Benign

0.22

Sift4G

Benign

0.36

Vest4

0.40

MutPred

0.39

Loss of methylation at K664 (P = 0.0036)

MVP

0.71

MPC

0.54

ClinPred

0.71

GERP RS

3.8

Varity_R

0.40

gMVP

0.65

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over