NM_001389466.1:c.376C>T

Variant names:

• chr16-89636538-C-T
• rs139374129
• NM_001389466.1:c.376C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001389466.1(DPEP1):​c.376C>T​(p.Arg126Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,612,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R126Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: DPEP1 NM_001389466.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.747
• Publications: 2 publications found

Genes affected

DPEP1 (HGNC:3002): (dipeptidase 1) The protein encoded by this gene is a kidney membrane enzyme involved in the metabolism of glutathione and other similar proteins by dipeptide hydrolysis. The encoded protein is known to regulate leukotriene activity by catalyzing the conversion of leukotriene D4 to leukotriene E4. This protein uses zinc as a cofactor and acts as a disulfide-linked homodimer. [provided by RefSeq, Dec 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001389466.1. 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
	DPEP1	NM_001389466.1	MANE Select	c.376C>T	p.Arg126Trp	missense	Exon 5 of 11	NP_001376395.1	P16444
	DPEP1	NM_001128141.3		c.376C>T	p.Arg126Trp	missense	Exon 5 of 11	NP_001121613.1	A0A140VJI3
	DPEP1	NM_001389467.1		c.376C>T	p.Arg126Trp	missense	Exon 5 of 11	NP_001376396.1	P16444

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPEP1	ENST00000690203.1	MANE Select	c.376C>T	p.Arg126Trp	missense	Exon 5 of 11	ENSP00000508584.1	P16444
	DPEP1	ENST00000261615.5	TSL:1	c.376C>T	p.Arg126Trp	missense	Exon 4 of 10	ENSP00000261615.4	P16444
	DPEP1	ENST00000393092.7	TSL:1	c.376C>T	p.Arg126Trp	missense	Exon 5 of 11	ENSP00000376807.3	P16444

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000523 AC: 13 AN: 248378 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000717

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1459802 Hom.: 0 Cov.: 34 AF XY: 0.0000592 AC XY: 43 AN XY: 726166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000747 AC: 83 AN: 1111678

Other (OTH) AF: 0.0000497 AC: 3 AN: 60358

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.75
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.10
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.095
MPC		0.13
ClinPred		0.44	T
GERP RS		-1.4
Varity_R		0.42
gMVP		0.67
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs139374129; hg19: chr16-89702946;