rs2800889

Positions:

• chr1-111500110-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000677.4(ADORA3):​c.797T>A​(p.Met266Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,614,210 control chromosomes in the GnomAD database, including 378 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.019 (29 hom., cov: 32)
  • Exomes 𝑓: 0.018 (349 hom.)
• Consequence: ADORA3 NM_000677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060951114).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0194 (2959/152334) while in subpopulation AFR AF= 0.0267 (1110/41572). AF 95% confidence interval is 0.0254. There are 29 homozygotes in gnomad4. There are 1365 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA3	NM_000677.4	c.797T>A	p.Met266Lys	missense_variant	2/2	ENST00000241356.5	NP_000668.1
TMIGD3	NM_020683.7	c.350+2895T>A		intron_variant		ENST00000369716.9	NP_065734.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA3	ENST00000241356.5	c.797T>A	p.Met266Lys	missense_variant	2/2	1	NM_000677.4	ENSP00000241356	P1
TMIGD3	ENST00000369716.9	c.350+2895T>A		intron_variant		1	NM_020683.7	ENSP00000358730	P1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2958 AN: 152216 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0172 AC: 4331 AN: 251436 Hom.: 59 AF XY: 0.0178 AC XY: 2424 AN XY: 135900

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00555

Gnomad SAS exome AF: 0.0281

Gnomad FIN exome AF: 0.00286

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0183 AC: 26773 AN: 1461876 Hom.: 349 Cov.: 38 AF XY: 0.0186 AC XY: 13515 AN XY: 727244

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.0261

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0194 AC: 2959 AN: 152334 Hom.: 29 Cov.: 32 AF XY: 0.0183 AC XY: 1365 AN XY: 74484

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0188 Hom.: 22

Bravo AF: 0.0208

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.0188 AC: 162

ExAC AF: 0.0178 AC: 2160

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0233

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.17
Eigen_PC	Benign	0.025
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.13
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.037	D
Vest4		0.19
ClinPred		0.020	T
GERP RS		5.4
Varity_R		0.60
gMVP		0.60

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: rs2800889; hg19: chr1-112042732; COSMIC: COSV53985915; COSMIC: COSV53985915;