15-65446980-T-C

Variant names:

• chr15-65446980-T-C
• rs750320894
• NM_130434.5:c.2553A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130434.5(DPP8):​c.2553A>G​(p.Ile851Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,446 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DPP8 NM_130434.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.870

Genes affected

DPP8 (HGNC:16490): (dipeptidyl peptidase 8) This gene encodes a member of the peptidase S9B family, a small family of dipeptidyl peptidases that are able to cleave peptide substrates at a prolyl bond. The encoded protein shares similarity with dipeptidyl peptidase IV in that it is ubiquitously expressed, and hydrolyzes the same substrates. These similarities suggest that, like dipeptidyl peptidase IV, this protein may play a role in T-cell activation and immune function. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPP8	NM_130434.5	c.2553A>G	p.Ile851Met	missense_variant	Exon 20 of 20	ENST00000300141.11	NP_569118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPP8	ENST00000300141.11	c.2553A>G	p.Ile851Met	missense_variant	Exon 20 of 20	1	NM_130434.5	ENSP00000300141.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247626 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000585

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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459446 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000898

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2601A>G (p.I867M) alteration is located in exon 21 (coding exon 20) of the DPP8 gene. This alteration results from a A to G substitution at nucleotide position 2601, causing the isoleucine (I) at amino acid position 867 to be replaced by a methionine (M). 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	0.87
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T;.;.;.;T
Eigen	Benign	0.052
Eigen_PC	Benign	0.0037
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	.;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-0.64	T
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.71
MutPred		0.66		Gain of disorder (P = 0.0652);.;.;.;Gain of disorder (P = 0.0652);
MVP		0.32
MPC		2.2
ClinPred		0.91	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.77

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: rs750320894; hg19: chr15-65739318;