Genetic Variant NM_001974.5:c.1615A>G (chr19-6919742-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001974.5(ADGRE1):c.1615A>G(p.Ile539Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 1,612,378 control chromosomes in the GnomAD database, including 492,849 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 41427 hom., cov: 28)

Exomes 𝑓: 0.79 ( 451422 hom. )

Consequence

ADGRE1
NM_001974.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0770

Publications

37 publications found

Variant links:

Genes affected

ADGRE1 (HGNC:3336): (adhesion G protein-coupled receptor E1) This gene encodes a protein that has a domain resembling seven transmembrane G protein-coupled hormone receptors (7TM receptors) at its C-terminus. The N-terminus of the encoded protein has six EGF-like modules, separated from the transmembrane segments by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ADGRE1 links:

LOC105372256 (HGNC:):

LOC105372256 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.3166597E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRE1	NM_001974.5 link	c.1615A>G	p.Ile539Val	missense_variant	Exon 13 of 21	ENST00000312053.9	NP_001965.3	Q14246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRE1	ENST00000312053.9 link	c.1615A>G	p.Ile539Val	missense_variant	Exon 13 of 21	1	NM_001974.5	ENSP00000311545.3		Q14246-1

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111172

AN:

151422

Hom.:

41408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.608

Gnomad AMI

AF:

0.740

Gnomad AMR

AF:

0.774

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.759

Gnomad FIN

AF:

0.803

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.784

Gnomad OTH

AF:

0.729

GnomAD2 exomes

AF:

0.771

AC:

193180

AN:

250662

AF XY:

0.771

show subpopulations

Gnomad AFR exome

AF:

0.603

Gnomad AMR exome

AF:

0.802

Gnomad ASJ exome

AF:

0.758

Gnomad EAS exome

AF:

0.784

Gnomad FIN exome

AF:

0.806

Gnomad NFE exome

AF:

0.781

Gnomad OTH exome

AF:

0.747

GnomAD4 exome

AF:

0.785

AC:

1146827

AN:

1460838

Hom.:

451422

Cov.:

AF XY:

0.784

AC XY:

569848

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.590

AC:

19737

AN:

33456

American (AMR)

AF:

0.797

AC:

35643

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.756

AC:

19737

AN:

26114

East Asian (EAS)

AF:

0.811

AC:

32196

AN:

39676

South Asian (SAS)

AF:

0.769

AC:

66311

AN:

86232

European-Finnish (FIN)

AF:

0.803

AC:

42841

AN:

53364

Middle Eastern (MID)

AF:

0.678

AC:

3900

AN:

5754

European-Non Finnish (NFE)

AF:

0.792

AC:

880486

AN:

1111202

Other (OTH)

AF:

0.762

AC:

45976

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11710

23421

35131

46842

58552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20718

41436

62154

82872

103590

<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:

0.734

AC:

111232

AN:

151540

Hom.:

41427

Cov.:

AF XY:

0.736

AC XY:

54440

AN XY:

73986

show subpopulations

African (AFR)

AF:

0.608

AC:

25070

AN:

41256

American (AMR)

AF:

0.774

AC:

11757

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.765

AC:

2650

AN:

3464

East Asian (EAS)

AF:

0.791

AC:

4040

AN:

5110

South Asian (SAS)

AF:

0.760

AC:

3647

AN:

4796

European-Finnish (FIN)

AF:

0.803

AC:

8420

AN:

10486

Middle Eastern (MID)

AF:

0.687

AC:

202

AN:

294

European-Non Finnish (NFE)

AF:

0.784

AC:

53251

AN:

67934

Other (OTH)

AF:

0.722

AC:

1522

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1404

2808

4211

5615

7019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.766

Hom.:

126327

Bravo

AF:

0.727

TwinsUK

AF:

0.801

AC:

2969

ALSPAC

AF:

0.798

AC:

3076

ESP6500AA

AF:

0.606

AC:

2671

ESP6500EA

AF:

0.788

AC:

6774

ExAC

AF:

0.764

AC:

92805

Asia WGS

AF:

0.661

AC:

2301

AN:

3478

EpiCase

AF:

0.763

EpiControl

AF:

0.772

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.060

.;.;T;.;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.56

T;T;T;T;T

MetaRNN

Benign

9.3e-7

T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

0.077

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.30

N;N;N;N;N

REVEL

Benign

0.043

Sift

Benign

0.81

T;T;T;T;T

Sift4G

Benign

0.67

T;T;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.13

MPC

0.20

ClinPred

0.0035

GERP RS

-0.14

Varity_R

0.069

gMVP

0.042

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over