rs569787719

chr7-154053046-G-Achr7-154053046-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_130797.4(DPP6):c.226G>A(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0226 in 1,058,538 control chromosomes in the GnomAD database, including 312 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 31)
  • Exomes 𝑓: 0.024 (286 hom.)
• Consequence: DPP6 NM_130797.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 3.63

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023885071).
• BP6: Variant 7-154053046-G-A is Benign according to our data. Variant chr7-154053046-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377138.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-154053046-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0161 (2407/149904) while in subpopulation SAS AF= 0.0288 (137/4760). AF 95% confidence interval is 0.0249. There are 26 homozygotes in gnomad4. There are 1253 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2406 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPP6	NM_130797.4	c.226G>A	p.Asp76Asn	missense_variant	1/26	ENST00000377770.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPP6	ENST00000377770.8	c.226G>A	p.Asp76Asn	missense_variant	1/26	1	NM_130797.4
DPP6	ENST00000406326.5	c.226G>A	p.Asp76Asn	missense_variant	1/6	1
DPP6	ENST00000404039.5	c.51+165312G>A		intron_variant		1
DPP6	ENST00000706130.1	c.60+304038G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2406 AN: 149792 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0155

GnomAD3 exomes AF: 0.0286 AC: 63 AN: 2200 Hom.: 0 AF XY: 0.0297 AC XY: 39 AN XY: 1312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0208

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0237 AC: 21490 AN: 908634 Hom.: 286 Cov.: 37 AF XY: 0.0236 AC XY: 10017 AN XY: 424422

Gnomad4 AFR exome AF: 0.00231

Gnomad4 AMR exome AF: 0.00804

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.0000901

Gnomad4 SAS exome AF: 0.0312

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0161 AC: 2407 AN: 149904 Hom.: 26 Cov.: 31 AF XY: 0.0171 AC XY: 1253 AN XY: 73148

Gnomad4 AFR AF: 0.00401

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0367

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0153

Alfa AF: 0.00577 Hom.: 0

Bravo AF: 0.0131

ExAC AF: 0.00978 AC: 134

Asia WGS AF: 0.00956 AC: 33 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 10, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.58	D
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;B
Vest4		0.13
MPC		0.42
ClinPred		0.072	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs569787719; hg19: chr7-153750131; COSMIC: COSV66710423; COSMIC: COSV66710423;