chr19-4682745-C-T

Position:

• chr19-4682745-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139159.5(DPP9):​c.2425G>A​(p.Gly809Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,456,062 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: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: DPP9 NM_139159.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPP9	NM_139159.5	c.2425G>A	p.Gly809Ser	missense_variant	20/22	ENST00000262960.14
DPP9-AS1	NR_164163.1	n.259-56C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPP9	ENST00000262960.14	c.2425G>A	p.Gly809Ser	missense_variant	20/22	1	NM_139159.5	P1
DPP9-AS1	ENST00000381796.1	n.259-56C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1456062 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 723764

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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.2425G>A (p.G809S) alteration is located in exon 20 (coding exon 18) of the DPP9 gene. This alteration results from a G to A substitution at nucleotide position 2425, causing the glycine (G) at amino acid position 809 to be replaced by a serine (S). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	.;D;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	.;D;.
Sift4G	Uncertain	0.0080	D;D;D
Vest4		0.91
MutPred		0.57		.;Loss of catalytic residue at G809 (P = 0.005);.;
MVP		0.51
MPC		2.2
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.40
gMVP		0.83

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

Other links and lift over

dbSNP: rs1021615821; hg19: chr19-4682757;