Genetic Variant ADORA2A:p.Gly147Ser (chr22-24440689-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000675.6(ADORA2A):c.439G>A(p.Gly147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,613,652 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 56 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 38 hom. )

Consequence

ADORA2A
NM_000675.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.00

Publications

7 publications found

Variant links:

Genes affected

ADORA2A (HGNC:263): (adenosine A2a receptor) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) superfamily, which is subdivided into classes and subtypes. The receptors are seven-pass transmembrane proteins that respond to extracellular cues and activate intracellular signal transduction pathways. This protein, an adenosine receptor of A2A subtype, uses adenosine as the preferred endogenous agonist and preferentially interacts with the G(s) and G(olf) family of G proteins to increase intracellular cAMP levels. It plays an important role in many biological functions, such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders. Alternative splicing results in multiple transcript variants. A read-through transcript composed of the upstream SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

ADORA2A links:

SPECC1L-ADORA2A (HGNC:49185): (SPECC1L-ADORA2A readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) genes on chromosome 22. The readthrough transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Jun 2013]

SPECC1L-ADORA2A links:

ADORA2A-AS1 (HGNC:37122): (ADORA2A antisense RNA 1)

ADORA2A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0018239319).

BP6

Variant 22-24440689-G-A is Benign according to our data. Variant chr22-24440689-G-A is described in ClinVar as Benign. ClinVar VariationId is 769157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2178/152280) while in subpopulation AFR AF = 0.0494 (2051/41552). AF 95% confidence interval is 0.0476. There are 56 homozygotes in GnomAd4. There are 1050 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2178 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000675.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADORA2A	NM_000675.6	MANE Select	c.439G>A	p.Gly147Ser	missense	Exon 3 of 3	NP_000666.2
ADORA2A	NM_001278497.2		c.439G>A	p.Gly147Ser	missense	Exon 4 of 4	NP_001265426.1	P29274
ADORA2A	NM_001278498.2		c.439G>A	p.Gly147Ser	missense	Exon 3 of 3	NP_001265427.1	X5DNB4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADORA2A	ENST00000337539.12	TSL:1 MANE Select	c.439G>A	p.Gly147Ser	missense	Exon 3 of 3	ENSP00000336630.6	P29274
ADORA2A	ENST00000618076.3	TSL:1	c.439G>A	p.Gly147Ser	missense	Exon 3 of 3	ENSP00000481552.1	P29274
SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.*1574G>A		non_coding_transcript_exon	Exon 20 of 20	ENSP00000351480.2	F8WAN1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2174

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00350

AC:

880

AN:

251202

AF XY:

0.00261

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00152

AC:

2217

AN:

1461372

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

926

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.0485

AC:

1623

AN:

33468

American (AMR)

AF:

0.00295

AC:

132

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000209

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000222

AC:

247

AN:

1111602

Other (OTH)

AF:

0.00306

AC:

185

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

141

281

422

562

703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0143

AC:

2178

AN:

152280

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1050

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0494

AC:

2051

AN:

41552

American (AMR)

AF:

0.00536

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68020

Other (OTH)

AF:

0.0138

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00501

Hom.:

Bravo

AF:

0.0162

ESP6500AA

AF:

0.0427

AC:

188

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00409

AC:

497

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

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

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.044

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.14

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.018

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.39

PhyloP100

-1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

0.31

REVEL

Benign

0.0060

Sift

Benign

1.0

Sift4G

Benign

0.99

Polyphen

0.0

Vest4

0.027

MVP

0.19

MPC

0.53

ClinPred

0.0012

GERP RS

-5.1

Varity_R

0.21

gMVP

0.24

Mutation Taster

=93/7

polymorphism

(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

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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