11-66486666-C-A

Position:

• chr11-66486666-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130443.4(DPP3):​c.487C>A​(p.Leu163Met) variant causes a missense change. The variant allele was found at a frequency of 0.000976 in 1,542,716 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: DPP3 NM_130443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.36

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=0.011111736).
• BP6: Variant 11-66486666-C-A is Benign according to our data. Variant chr11-66486666-C-A is described in ClinVar as [Benign]. Clinvar id is 710005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00534 (813/152176) while in subpopulation AFR AF= 0.018 (748/41520). AF 95% confidence interval is 0.0169. There are 6 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPP3	NM_130443.4	c.487C>A	p.Leu163Met	missense_variant	4/18	ENST00000531863.6	NP_569710.2
DPP3	NM_005700.5	c.487C>A	p.Leu163Met	missense_variant	4/18		NP_005691.2
DPP3	NM_001256670.2	c.397C>A	p.Leu133Met	missense_variant	3/17		NP_001243599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPP3	ENST00000531863.6	c.487C>A	p.Leu163Met	missense_variant	4/18	1	NM_130443.4	ENSP00000432782	P1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 812 AN: 152058 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00138 AC: 273 AN: 197718 Hom.: 2 AF XY: 0.00116 AC XY: 125 AN XY: 107930

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.000962

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.000909

GnomAD4 exome AF: 0.000498 AC: 692 AN: 1390540 Hom.: 4 Cov.: 31 AF XY: 0.000473 AC XY: 326 AN XY: 689672

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000919

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000929

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152176 Hom.: 6 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74392

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000912 Hom.: 0

Bravo AF: 0.00647

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00157 AC: 190

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	0.26
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;T;T;T;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D;D;D;D;D
Polyphen		1.0, 0.98	.;D;D;.;.;.;.;.
Vest4		0.43
MVP		0.31
ClinPred		0.023	T
GERP RS		4.1
Varity_R		0.44
gMVP		0.28

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: rs112484606; hg19: chr11-66254137;