rs2789537

Positions:

• chr1-111500517-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_000677.4(ADORA3):​c.390C>T​(p.Ala130=) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.961

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA3	NM_000677.4	c.390C>T	p.Ala130=	synonymous_variant	2/2	ENST00000241356.5	NP_000668.1
TMIGD3	NM_020683.7	c.350+2488C>T		intron_variant		ENST00000369716.9	NP_065734.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA3	ENST00000241356.5	c.390C>T	p.Ala130=	synonymous_variant	2/2	1	NM_000677.4	ENSP00000241356	P1
TMIGD3	ENST00000369716.9	c.350+2488C>T		intron_variant		1	NM_020683.7	ENSP00000358730	P1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2842 AN: 152178 Hom.: 27 Cov.: 32

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

GnomAD3 exomes AF: 0.0170 AC: 4229 AN: 249210 Hom.: 59 AF XY: 0.0177 AC XY: 2382 AN XY: 134928

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 SAS exome AF: 0.0281

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.: 36 AF XY: 0.0183 AC XY: 13306 AN XY: 727238

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.0262

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0187 AC: 2843 AN: 152296 Hom.: 27 Cov.: 32 AF XY: 0.0175 AC XY: 1307 AN XY: 74476

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0194 Hom.: 17

Bravo AF: 0.0201

Asia WGS AF: 0.0100 AC: 36 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
DANN	Benign	0.64

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

LitVar

Other links and lift over

dbSNP: rs2789537; hg19: chr1-112043139;