Genetic Variant DPP9:p.Gly675Cys (chr19-4685634-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_139159.5(DPP9):c.2023G>T(p.Gly675Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G675S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DPP9
NM_139159.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.86

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

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.2023G>T	p.Gly675Cys	missense	Exon 17 of 22	NP_631898.3
DPP9	NM_001384611.1		c.2023G>T	p.Gly675Cys	missense	Exon 16 of 21	NP_001371540.1	Q86TI2-2
DPP9	NM_001384612.1		c.2023G>T	p.Gly675Cys	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.2023G>T	p.Gly675Cys	missense	Exon 17 of 22	ENSP00000262960.8	Q86TI2-2
DPP9	ENST00000600621.6	TSL:4	c.2023G>T	p.Gly675Cys	missense	Exon 17 of 22	ENSP00000472549.2	Q86TI2-2
DPP9	ENST00000601130.6	TSL:4	c.2023G>T	p.Gly675Cys	missense	Exon 18 of 23	ENSP00000471629.2	Q86TI2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000428

AC:

AN:

233660

AF XY:

0.00000787

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454156

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

43398

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

84964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108930

Other (OTH)

AF:

0.00

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

4.2

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.2

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.97

MutPred

0.88

Loss of catalytic residue at L680 (P = 0.1657)

MVP

0.61

MPC

1.2

ClinPred

1.0

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.85

gMVP

0.98

Mutation Taster

=9/91

disease causing

(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