rs35511654

chr1-111500165-T-G

Variant summary

Our verdict is Benign. Variant got -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. 11/17 in silico tools predict 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 0.097 (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

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=0.0017711222).
• 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/exons	MANE	UniProt
ADORA3	NM_000677.4	c.742A>C	p.Ile248Leu	missense_variant	2/2	ENST00000241356.5
TMIGD3	NM_020683.7	c.350+2840A>C		intron_variant		ENST00000369716.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADORA3	ENST00000241356.5	c.742A>C	p.Ile248Leu	missense_variant	2/2	1	NM_000677.4	P1
TMIGD3	ENST00000369716.9	c.350+2840A>C		intron_variant		1	NM_020683.7	P1

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

GnomAD3 exomes AF: 0.0945 AC: 23749 AN: 251346 Hom.: 1493 AF XY: 0.0961 AC XY: 13057 AN XY: 135860

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 SAS exome AF: 0.0316

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

Gnomad4 AFR exome AF: 0.0582

Gnomad4 AMR exome AF: 0.0690

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0332

Gnomad4 FIN exome AF: 0.0844

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.113

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

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.0984

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.0772

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.106

Alfa AF: 0.124 Hom.: 2069

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
MutationTaster	Benign	0.21	P;P;P
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

Publications

LitVar

Other links and lift over

dbSNP: rs35511654; hg19: chr1-112042787;