Genetic Variant NM_000677.4:c.390C>T (chr1-111500517-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The NM_000677.4(ADORA3):c.390C>T(p.Ala130Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,170 control chromosomes in the GnomAD database, including 366 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 0.019 ( 27 hom., cov: 32)

Exomes 𝑓: 0.018 ( 339 hom. )

Consequence

ADORA3
NM_000677.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.961

Publications

5 publications found

Variant links:

Genes affected

ADORA3 (HGNC:268): (adenosine A3 receptor) This gene encodes a protein that belongs to the family of adenosine receptors, which are G-protein-coupled receptors that are involved in a variety of intracellular signaling pathways and physiological functions. The receptor encoded by this gene mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death. Alternative splicing results in multiple transcript variants. This gene shares its 5' terminal exon with some transcripts from overlapping GeneID:57413, which encodes an immunoglobulin domain-containing protein. [provided by RefSeq, Nov 2014]

ADORA3 links:

TMIGD3 (HGNC:51375): (transmembrane and immunoglobulin domain containing 3) This gene encodes a transmembrane and immunoglobulin domain-containing protein. Alternative splicing results in multiple transcript variants, one of which shares its 5' terminal exon with that of the overlapping adenosine A3 receptor gene (GeneID:140), thus resulting in a fusion product. [provided by RefSeq, Nov 2014]

TMIGD3 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP7

Synonymous conserved (PhyloP=-0.961 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0187 (2843/152296) while in subpopulation AFR AF = 0.0249 (1035/41536). AF 95% confidence interval is 0.0237. There are 27 homozygotes in GnomAd4. There are 1307 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADORA3	NM_000677.4 link	c.390C>T	p.Ala130Ala	synonymous_variant	Exon 2 of 2	ENST00000241356.5	NP_000668.1	P0DMS8-1
TMIGD3	NM_020683.7 link	c.350+2488C>T		intron_variant	Intron 1 of 5	ENST00000369716.9	NP_065734.5	P0DMS9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADORA3	ENST00000241356.5 link	c.390C>T	p.Ala130Ala	synonymous_variant	Exon 2 of 2	1	NM_000677.4	ENSP00000241356.4		P0DMS8-1
TMIGD3	ENST00000369716.9 link	c.350+2488C>T		intron_variant	Intron 1 of 5	1	NM_020683.7	ENSP00000358730.4		P0DMS9-2

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2842

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00999

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0170

AC:

4229

AN:

249210

AF XY:

0.0177

show subpopulations

Gnomad AFR exome

AF:

0.0264

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00549

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0167

GnomAD4 exome

AF:

0.0180

AC:

26328

AN:

1461874

Hom.:

339

Cov.:

AF XY:

0.0183

AC XY:

13306

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0251

AC:

840

AN:

33480

American (AMR)

AF:

0.0112

AC:

501

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

369

AN:

26136

East Asian (EAS)

AF:

0.0149

AC:

590

AN:

39698

South Asian (SAS)

AF:

0.0262

AC:

2256

AN:

86258

European-Finnish (FIN)

AF:

0.00281

AC:

150

AN:

53420

Middle Eastern (MID)

AF:

0.0342

AC:

197

AN:

5766

European-Non Finnish (NFE)

AF:

0.0183

AC:

20354

AN:

1111996

Other (OTH)

AF:

0.0177

AC:

1071

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1546

3092

4638

6184

7730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.0187

AC:

2843

AN:

152296

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1307

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0249

AC:

1035

AN:

41536

American (AMR)

AF:

0.0137

AC:

210

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.0102

AC:

AN:

5194

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4822

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1296

AN:

68038

Other (OTH)

AF:

0.0223

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

149

298

446

595

744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0194

Hom.:

Bravo

AF:

0.0201

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0230

EpiControl

AF:

0.0228

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

6.8

(source)

DANN

Benign

0.64

PhyloP100

-0.96

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over