rs35511654

Variant names:

• chr1-111500165-T-G
• rs35511654
• NM_000677.4:c.742A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000677.4(ADORA3):​c.742A>C​(p.Ile248Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,614,070 control chromosomes in the GnomAD database, including 12,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.097 (830 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11835 hom.)
• Consequence: ADORA3 NM_000677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• Publications: 21 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017711222).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADORA3	NM_000677.4	c.742A>C	p.Ile248Leu	missense_variant	Exon 2 of 2	ENST00000241356.5	NP_000668.1
TMIGD3	NM_020683.7	c.350+2840A>C		intron_variant	Intron 1 of 5	ENST00000369716.9	NP_065734.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADORA3	ENST00000241356.5	c.742A>C	p.Ile248Leu	missense_variant	Exon 2 of 2	1	NM_000677.4	ENSP00000241356.4
TMIGD3	ENST00000369716.9	c.350+2840A>C		intron_variant	Intron 1 of 5	1	NM_020683.7	ENSP00000358730.4

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14725 AN: 152092 Hom.: 830 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0986

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0945 AC: 23749 AN: 251346 AF XY: 0.0961

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.0654

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0793

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.121 AC: 176782 AN: 1461860 Hom.: 11835 Cov.: 39 AF XY: 0.119 AC XY: 86179 AN XY: 727230

African (AFR) AF: 0.0582 AC: 1949 AN: 33478

American (AMR) AF: 0.0690 AC: 3084 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4053 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0332 AC: 2860 AN: 86258

European-Finnish (FIN) AF: 0.0844 AC: 4510 AN: 53420

Middle Eastern (MID) AF: 0.178 AC: 1029 AN: 5768

European-Non Finnish (NFE) AF: 0.137 AC: 152472 AN: 1111980

Other (OTH) AF: 0.113 AC: 6815 AN: 60396

GnomAD4 genome AF: 0.0968 AC: 14728 AN: 152210 Hom.: 830 Cov.: 32 AF XY: 0.0933 AC XY: 6939 AN XY: 74410

African (AFR) AF: 0.0592 AC: 2460 AN: 41524

American (AMR) AF: 0.0984 AC: 1505 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0311 AC: 150 AN: 4826

European-Finnish (FIN) AF: 0.0772 AC: 817 AN: 10584

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8905 AN: 68010

Other (OTH) AF: 0.106 AC: 224 AN: 2112

Alfa AF: 0.118 Hom.: 2606

Bravo AF: 0.0971

TwinsUK AF: 0.136 AC: 506

ALSPAC AF: 0.134 AC: 515

ESP6500AA AF: 0.0581 AC: 256

ESP6500EA AF: 0.137 AC: 1175

ExAC AF: 0.0947 AC: 11498

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.96	L
PhyloP100		3.2
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.042	D
Vest4		0.14
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.23
gMVP		0.40

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

Other links and lift over

dbSNP: rs35511654; hg19: chr1-112042787; COSMIC: COSV107278938; COSMIC: COSV107278938;