19-4684663-C-T

Position:

• chr19-4684663-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_139159.5(DPP9):​c.2178G>A​(p.Met726Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPP9 NM_139159.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.76

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-4684663-C-T is Pathogenic according to our data. Variant chr19-4684663-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3256926.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPP9	NM_139159.5	c.2178G>A	p.Met726Ile	missense_variant, splice_region_variant	18/22	ENST00000262960.14	NP_631898.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPP9	ENST00000262960.14	c.2178G>A	p.Met726Ile	missense_variant, splice_region_variant	18/22	1	NM_139159.5	ENSP00000262960.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Susceptibility to severe COVID-19 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Medicine Center, Medical University of Sofia

Jul 22, 2024

Novel (unreported in gnomAD or dbSNP until April 2024) variant found in severely infected COVID-19 Bulgarian patients in a research study. Variant is classified as likely pathogenic according to the ACMG criteria: PM1,PM2,PP3,PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.5	.;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	.;D;.
Sift4G	Uncertain	0.029	D;D;D
Vest4		0.85
MutPred		0.71		.;Loss of ubiquitination at K723 (P = 0.0573);.;
MVP		0.41
MPC		0.79
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4684675;