11-66482427-G-A

Position:

• chr11-66482427-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130443.4(DPP3):​c.227G>A​(p.Arg76His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,608,834 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (108 hom.)
• Consequence: DPP3 NM_130443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.945

Genes affected

DPP3 (HGNC:3008): (dipeptidyl peptidase 3) This gene encodes a protein that is a member of the M49 family of metallopeptidases. This cytoplasmic protein binds a single zinc ion with its zinc-binding motif (HELLGH) and has post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Increased activity of this protein is associated with endometrial and ovarian cancers. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029726326).
• BP6: Variant 11-66482427-G-A is Benign according to our data. Variant chr11-66482427-G-A is described in ClinVar as [Benign]. Clinvar id is 786198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPP3	NM_130443.4	c.227G>A	p.Arg76His	missense_variant	2/18	ENST00000531863.6	NP_569710.2
DPP3	NM_005700.5	c.227G>A	p.Arg76His	missense_variant	2/18		NP_005691.2
DPP3	NM_001256670.2	c.227G>A	p.Arg76His	missense_variant	2/17		NP_001243599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPP3	ENST00000531863.6	c.227G>A	p.Arg76His	missense_variant	2/18	1	NM_130443.4	ENSP00000432782	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3149 AN: 152190 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00558 AC: 1379 AN: 247048 Hom.: 46 AF XY: 0.00395 AC XY: 529 AN XY: 134004

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00212 AC: 3093 AN: 1456526 Hom.: 108 Cov.: 31 AF XY: 0.00179 AC XY: 1294 AN XY: 724852

Gnomad4 AFR exome AF: 0.0744

Gnomad4 AMR exome AF: 0.00452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.0208 AC: 3162 AN: 152308 Hom.: 96 Cov.: 32 AF XY: 0.0199 AC XY: 1481 AN XY: 74482

Gnomad4 AFR AF: 0.0717

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00444 Hom.: 51

Bravo AF: 0.0243

ESP6500AA AF: 0.0686 AC: 302

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00684 AC: 830

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;T;T;.;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D
REVEL	Benign	0.095
Sift	Uncertain	0.018	D;D;D;D;D;D;D
Sift4G	Uncertain	0.050	T;T;D;T;T;T;T
Polyphen		0.025, 0.0040	.;B;B;.;.;.;.
Vest4		0.13
MVP		0.25
ClinPred		0.035	T
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.20

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: rs11826683; hg19: chr11-66249898;