Genetic Variant ADGRD1:c.-83C>T (chr12-131084560-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP4_StrongBS1BS2

The ENST00000335486.10(ADGRD1):c.-83C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0272 in 1,614,052 control chromosomes in the GnomAD database, including 748 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 43 hom., cov: 32)

Exomes 𝑓: 0.028 ( 705 hom. )

Consequence

ADGRD1
ENST00000335486.10 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.66

Publications

10 publications found

Variant links:

Genes affected

ADGRD1 (HGNC:19893): (adhesion G protein-coupled receptor D1) The adhesion G-protein-coupled receptors (GPCRs), including GPR133, are membrane-bound proteins with long N termini containing multiple domains. GPCRs, or GPRs, contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins (summary by Bjarnadottir et al., 2004 [PubMed 15203201]).[supplied by OMIM, Nov 2010]

ADGRD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.007883668).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0217 (3305/152278) while in subpopulation NFE AF = 0.0304 (2067/68018). AF 95% confidence interval is 0.0293. There are 43 homozygotes in GnomAd4. There are 1643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000335486.10. 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
	ADGRD1	NM_198827.5	MANE Select	c.1568C>T	p.Ser523Leu	missense	Exon 15 of 25	NP_942122.2
	ADGRD1	NM_001330497.2		c.1664C>T	p.Ser555Leu	missense	Exon 16 of 26	NP_001317426.1	Q6QNK2-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRD1	ENST00000335486.10	TSL:1	c.-83C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	ENSP00000334127.7	H0Y2U9
ADGRD1	ENST00000261654.10	TSL:1 MANE Select	c.1568C>T	p.Ser523Leu	missense	Exon 15 of 25	ENSP00000261654.5	Q6QNK2-1
ADGRD1	ENST00000535015.5	TSL:1	c.1664C>T	p.Ser555Leu	missense	Exon 16 of 26	ENSP00000444425.1	Q6QNK2-4

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3304

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00512

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0168

GnomAD2 exomes

AF:

0.0249

AC:

6269

AN:

251326

AF XY:

0.0254

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.0228

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0364

Gnomad NFE exome

AF:

0.0315

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0278

AC:

40580

AN:

1461774

Hom.:

705

Cov.:

AF XY:

0.0278

AC XY:

20193

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33480

American (AMR)

AF:

0.0253

AC:

1131

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

506

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0229

AC:

1975

AN:

86256

European-Finnish (FIN)

AF:

0.0367

AC:

1961

AN:

53386

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0300

AC:

33328

AN:

1111936

Other (OTH)

AF:

0.0245

AC:

1480

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2033

4067

6100

8134

10167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1210

2420

3630

4840

6050

<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:

0.0217

AC:

3305

AN:

152278

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1643

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00510

AC:

212

AN:

41562

American (AMR)

AF:

0.0263

AC:

403

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.000967

AC:

AN:

5168

South Asian (SAS)

AF:

0.0273

AC:

132

AN:

4828

European-Finnish (FIN)

AF:

0.0334

AC:

355

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0304

AC:

2067

AN:

68018

Other (OTH)

AF:

0.0166

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0245

Hom.:

185

Bravo

AF:

0.0201

TwinsUK

AF:

0.0329

AC:

122

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0305

AC:

262

ExAC

AF:

0.0259

AC:

3141

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.62

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0079

MetaSVM

Uncertain

-0.093

PhyloP100

6.7

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.032

Polyphen

0.98

Vest4

0.84

MPC

0.62

ClinPred

0.038

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.58

gMVP

0.77

Mutation Taster

=78/22

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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