1-203165554-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000674.3(ADORA1):c.635A>G(p.Asn212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,934 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N212D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: ADORA1 NM_000674.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.720

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011990994).
• BP6: Variant 1-203165554-A-G is Benign according to our data. Variant chr1-203165554-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3046184.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 302 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADORA1	NM_000674.3	c.635A>G	p.Asn212Ser	missense_variant	4/4	ENST00000337894.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADORA1	ENST00000337894.9	c.635A>G	p.Asn212Ser	missense_variant	4/4	2	NM_000674.3	P1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00125 AC: 315 AN: 251376 Hom.: 0 AF XY: 0.00138 AC XY: 188 AN XY: 135848

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00230 AC: 3359 AN: 1461672 Hom.: 6 Cov.: 32 AF XY: 0.00226 AC XY: 1642 AN XY: 727112

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00270

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74456

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00196 Hom.: 1

Bravo AF: 0.00221

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00127 AC: 154

EpiCase AF: 0.00284

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ADORA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2023

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	4.2
Dann	Benign	0.80
DEOGEN2	Benign	0.28	T;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.85	T;T;T;.
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.042
MVP		0.66
MPC		0.57
ClinPred		0.012	T
GERP RS		-5.3
Varity_R		0.12
gMVP		0.36

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: rs75070458; hg19: chr1-203134682; COSMIC: COSV55142336; COSMIC: COSV55142336;