1-203128998-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000674.3(ADORA1):c.157G>A(p.Val53Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,614,182 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: ADORA1 NM_000674.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.21

Genes affected

ADORA1 (HGNC:262): (adenosine A1 receptor) The protein encoded by this gene is an adenosine receptor that belongs to the G-protein coupled receptor 1 family. There are 3 types of adenosine receptors, each with a specific pattern of ligand binding and tissue distribution, and together they regulate a diverse set of physiologic functions. The type A1 receptors inhibit adenylyl cyclase, and play a role in the fertilization process. Animal studies also suggest a role for A1 receptors in kidney function and ethanol intoxication. Transcript variants with alternative splicing in the 5' UTR have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013308197).
• BP6: Variant 1-203128998-G-A is Benign according to our data. Variant chr1-203128998-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 725560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADORA1	NM_000674.3	c.157G>A	p.Val53Met	missense_variant	3/4	ENST00000337894.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADORA1	ENST00000337894.9	c.157G>A	p.Val53Met	missense_variant	3/4	2	NM_000674.3	P1
ADORA1	ENST00000309502.7	c.157G>A	p.Val53Met	missense_variant	5/6	1		P1
ADORA1	ENST00000367236.8	c.157G>A	p.Val53Met	missense_variant	2/3	1		P1
ADORA1	ENST00000367235.1	c.157G>A	p.Val53Met	missense_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000557 AC: 140 AN: 251398 Hom.: 1 AF XY: 0.000324 AC XY: 44 AN XY: 135876

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000189 AC: 277 AN: 1461866 Hom.: 3 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 727236

Gnomad4 AFR exome AF: 0.00639

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74486

Gnomad4 AFR AF: 0.00667

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000316 Hom.: 0

Bravo AF: 0.00219

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ADORA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;.;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N;N;.;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D;D;.;D;T
Sift4G	Uncertain	0.0040	D;D;.;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.48
MVP		0.78
MPC		1.3
ClinPred		0.027	T
GERP RS		5.2
Varity_R		0.57
gMVP		0.48

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: rs61731146; hg19: chr1-203098126; COSMIC: COSV100526824; COSMIC: COSV100526824;