7-154053047-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_130797.4(DPP6):c.227A>T(p.Asp76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,052,324 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.011 ( 18 hom., cov: 31)

Exomes 𝑓: 0.015 ( 124 hom. )

Consequence

DPP6
NM_130797.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.41

Variant links:

Genes affected

DPP6 (HGNC:3010): (dipeptidyl peptidase like 6) This gene encodes a single-pass type II membrane protein that is a member of the peptidase S9B family of serine proteases. This protein has no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it does bind specific voltage-gated potassium channels and alters their expression and biophysical properties. Variations in this gene may be associated with susceptibility to amyotrophic lateral sclerosis and with idiopathic ventricular fibrillation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

DPP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031171143).

BP6

Variant 7-154053047-A-T is Benign according to our data. Variant chr7-154053047-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr7-154053047-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0148 (13392/903676) while in subpopulation MID AF= 0.03 (64/2132). AF 95% confidence interval is 0.0241. There are 124 homozygotes in gnomad4_exome. There are 6224 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1605 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPP6	NM_130797.4 link	c.227A>T	p.Asp76Val	missense_variant	Exon 1 of 26	ENST00000377770.8	NP_570629.2	P42658-1Q8IYG9A7E2E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DPP6	ENST00000377770.8 link	c.227A>T	p.Asp76Val	missense_variant	Exon 1 of 26	1	NM_130797.4	ENSP00000367001.3	P42658-1
DPP6	ENST00000406326.5 link	c.227A>T	p.Asp76Val	missense_variant	Exon 1 of 6	1		ENSP00000384393.1	Q8IYG9
DPP6	ENST00000404039.5 link	c.51+165313A>T		intron_variant	Intron 1 of 25	1		ENSP00000385578.1	E9PF59
DPP6	ENST00000706130.1 link	c.60+304039A>T		intron_variant	Intron 2 of 26			ENSP00000516215.1	A0A994J7K0

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1606

AN:

148536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00573

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.0190

GnomAD3 exomes

AF:

0.00907

AC:

AN:

2204

Hom.:

AF XY:

0.0137

AC XY:

AN XY:

1312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00500

Gnomad FIN exome

AF:

0.00335

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0476

GnomAD4 exome

AF:

0.0148

AC:

13392

AN:

903676

Hom.:

124

Cov.:

AF XY:

0.0148

AC XY:

6224

AN XY:

421800

show subpopulations

Gnomad4 AFR exome

AF:

0.00199

Gnomad4 AMR exome

AF:

0.0145

Gnomad4 ASJ exome

AF:

0.0261

Gnomad4 EAS exome

AF:

0.0000952

Gnomad4 SAS exome

AF:

0.00558

Gnomad4 FIN exome

AF:

0.00416

Gnomad4 NFE exome

AF:

0.0155

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

AF:

0.0108

AC:

1605

AN:

148648

Hom.:

Cov.:

AF XY:

0.00994

AC XY:

721

AN XY:

72522

show subpopulations

Gnomad4 AFR

AF:

0.00299

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00552

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.0188

Alfa

AF:

0.00307

Hom.:

Bravo

AF:

0.0122

ExAC

AF:

0.00325

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Sep 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.018

T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.61

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.025

D;T

Sift4G

Benign

0.15

T;T

Polyphen

0.12

B;B

Vest4

0.24

MVP

0.42

MPC

0.59

ClinPred

0.021

GERP RS

2.0

Varity_R

0.20

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over