rs572667303

Variant names:

• chr7-154053047-A-T
• rs572667303
• NM_130797.4:c.227A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-154053047-A-T
• chr7-154053047-A-C
• chr7-154053047-A-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/19 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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 31)
  • Exomes 𝑓: 0.015 (124 hom.)
• Consequence: DPP6 NM_130797.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.41
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant primary microcephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ventricular fibrillation, paroxysmal familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability, autosomal dominant 33

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000203335 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 252780.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 6224 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1605 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130797.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPP6	NM_130797.4	MANE Select	c.227A>T	p.Asp76Val	missense	Exon 1 of 26	NP_570629.2	P42658-1
	DPP6	NM_001290253.2		c.227A>T	p.Asp76Val	missense	Exon 1 of 6	NP_001277182.1	Q8IYG9
	DPP6	NM_001364497.2		c.60+304039A>T		intron	N/A	NP_001351426.1	A0A994J7K0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPP6	ENST00000377770.8	TSL:1 MANE Select	c.227A>T	p.Asp76Val	missense	Exon 1 of 26	ENSP00000367001.3	P42658-1
	DPP6	ENST00000406326.5	TSL:1	c.227A>T	p.Asp76Val	missense	Exon 1 of 6	ENSP00000384393.1	Q8IYG9
	DPP6	ENST00000404039.5	TSL:1	c.51+165313A>T		intron	N/A	ENSP00000385578.1	E9PF59

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1606 AN: 148536 Hom.: 18 Cov.: 31

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

GnomAD2 exomes AF: 0.00907 AC: 20 AN: 2204 AF XY: 0.0137

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 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.: 37 AF XY: 0.0148 AC XY: 6224 AN XY: 421800

African (AFR) AF: 0.00199 AC: 35 AN: 17620

American (AMR) AF: 0.0145 AC: 41 AN: 2820

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 192 AN: 7354

East Asian (EAS) AF: 0.0000952 AC: 1 AN: 10506

South Asian (SAS) AF: 0.00558 AC: 101 AN: 18088

European-Finnish (FIN) AF: 0.00416 AC: 34 AN: 8172

Middle Eastern (MID) AF: 0.0300 AC: 64 AN: 2132

European-Non Finnish (NFE) AF: 0.0155 AC: 12466 AN: 805578

Other (OTH) AF: 0.0146 AC: 458 AN: 31406

GnomAD4 genome AF: 0.0108 AC: 1605 AN: 148648 Hom.: 18 Cov.: 31 AF XY: 0.00994 AC XY: 721 AN XY: 72522

African (AFR) AF: 0.00299 AC: 121 AN: 40528

American (AMR) AF: 0.0158 AC: 237 AN: 14970

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 114 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4926

South Asian (SAS) AF: 0.00552 AC: 26 AN: 4714

European-Finnish (FIN) AF: 0.00217 AC: 21 AN: 9696

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1041 AN: 67098

Other (OTH) AF: 0.0188 AC: 39 AN: 2070

Alfa AF: 0.00307 Hom.: 1

Bravo AF: 0.0122

ExAC AF: 0.00325 AC: 45

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.79
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.61	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Sift4G	Benign	0.15	T
Polyphen		0.12	B
Vest4		0.24
MVP		0.42
MPC		0.59
ClinPred		0.021	T
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

Other links and lift over

dbSNP: rs572667303; hg19: chr7-153750132; COSMIC: COSV66726197; COSMIC: COSV66726197;