NM_130797.4:c.227A>G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_130797.4(DPP6):​c.227A>G​(p.Asp76Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 903,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DPP6 NM_130797.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1423023).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPP6	NM_130797.4	c.227A>G	p.Asp76Gly	missense_variant	Exon 1 of 26	ENST00000377770.8	NP_570629.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPP6	ENST00000377770.8	c.227A>G	p.Asp76Gly	missense_variant	Exon 1 of 26	1	NM_130797.4	ENSP00000367001.3
DPP6	ENST00000406326.5	c.227A>G	p.Asp76Gly	missense_variant	Exon 1 of 6	1		ENSP00000384393.1
DPP6	ENST00000404039.5	c.51+165313A>G		intron_variant	Intron 1 of 25	1		ENSP00000385578.1
DPP6	ENST00000706130.1	c.60+304039A>G		intron_variant	Intron 2 of 26			ENSP00000516215.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000111 AC: 10 AN: 903698 Hom.: 0 Cov.: 37 AF XY: 0.0000166 AC XY: 7 AN XY: 421806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000124

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.79
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.58	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.11
Sift	Benign	0.035	D;T
Sift4G	Benign	0.20	T;T
Polyphen		0.045	B;B
Vest4		0.17
MutPred		0.19		Gain of glycosylation at S75 (P = 0.0275);Gain of glycosylation at S75 (P = 0.0275);
MVP		0.39
MPC		0.54
ClinPred		0.85	D
GERP RS		2.0
Varity_R		0.19
gMVP		0.14

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: rs572667303; hg19: chr7-153750132;