Genetic Variant NM_001935.4:c.1987+4T>C (chr2-162008558-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001935.4(DPP4):c.1987+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,612,816 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 90 hom. )

Consequence

DPP4
NM_001935.4 splice_region, intron

Scores

Splicing: ADA: 0.00007068

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.570

Publications

5 publications found

Variant links:

Genes affected

DPP4 (HGNC:3009): (dipeptidyl peptidase 4) The DPP4 gene encodes dipeptidyl peptidase 4, which is identical to adenosine deaminase complexing protein-2, and to the T-cell activation antigen CD26. It is an intrinsic type II transmembrane glycoprotein and a serine exopeptidase that cleaves X-proline dipeptides from the N-terminus of polypeptides. Dipeptidyl peptidase 4 is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19. [provided by RefSeq, Apr 2020]

DPP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-162008558-A-G is Benign according to our data. Variant chr2-162008558-A-G is described in ClinVar as Benign. ClinVar VariationId is 715707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001935.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DPP4	NM_001935.4	MANE Select	c.1987+4T>C	splice_region intron	N/A	NP_001926.2
DPP4	NM_001379604.1		c.1984+4T>C	splice_region intron	N/A	NP_001366533.1	A0A7I2V2X8
DPP4	NM_001379605.1		c.1981+4T>C	splice_region intron	N/A	NP_001366534.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DPP4	ENST00000360534.8	TSL:1 MANE Select	c.1987+4T>C	splice_region intron	N/A	ENSP00000353731.3	P27487
DPP4	ENST00000434918.6	TSL:1	n.*1706+4T>C	splice_region intron	N/A	ENSP00000402259.2	F8WE17
DPP4	ENST00000676810.1		c.1984+4T>C	splice_region intron	N/A	ENSP00000503161.1	A0A7I2V2X8

Frequencies

GnomAD3 genomes

AF:

0.00263

AC:

399

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000750

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00958

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0291

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00521

AC:

1306

AN:

250884

AF XY:

0.00425

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0256

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000697

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00267

AC:

3907

AN:

1460714

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1880

AN XY:

726724

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33428

American (AMR)

AF:

0.0172

AC:

767

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.000881

AC:

AN:

26100

East Asian (EAS)

AF:

0.0563

AC:

2233

AN:

39684

South Asian (SAS)

AF:

0.00241

AC:

208

AN:

86228

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000469

AC:

521

AN:

1111120

Other (OTH)

AF:

0.00219

AC:

132

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

213

426

638

851

1064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00263

AC:

400

AN:

152102

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

214

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

41472

American (AMR)

AF:

0.00963

AC:

147

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.0292

AC:

151

AN:

5172

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

67978

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00393

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.000437

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.8

(source)

DANN

Benign

0.83

PhyloP100

-0.57

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000071

dbscSNV1_RF

Benign

0.082

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over