1-203165293-C-A

Variant names:

• chr1-203165293-C-A
• rs79599913
• NM_000674.3:c.374C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000674.3(ADORA1):​c.374C>A​(p.Ala125Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A125V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADORA1 NM_000674.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000674.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA1	NM_000674.3	MANE Select	c.374C>A	p.Ala125Glu	missense	Exon 4 of 4	NP_000665.1	P30542-1
	ADORA1	NM_001048230.2		c.374C>A	p.Ala125Glu	missense	Exon 3 of 3	NP_001041695.1	P30542-1
	ADORA1	NM_001365065.1		c.170C>A	p.Ala57Glu	missense	Exon 3 of 3	NP_001351994.1	B7Z1L9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA1	ENST00000337894.9	TSL:2 MANE Select	c.374C>A	p.Ala125Glu	missense	Exon 4 of 4	ENSP00000338435.4	P30542-1
	ADORA1	ENST00000309502.7	TSL:1	c.374C>A	p.Ala125Glu	missense	Exon 6 of 6	ENSP00000308549.3	P30542-1
	ADORA1	ENST00000367236.8	TSL:1	c.374C>A	p.Ala125Glu	missense	Exon 3 of 3	ENSP00000356205.4	P30542-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419042 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32138

American (AMR) AF: 0.00 AC: 0 AN: 39050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23140

East Asian (EAS) AF: 0.00 AC: 0 AN: 39290

South Asian (SAS) AF: 0.00 AC: 0 AN: 78954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090702

Other (OTH) AF: 0.0000171 AC: 1 AN: 58378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.21
Sift	Benign	0.28	T
Sift4G	Benign	0.29	T
Polyphen		0.10	B
Vest4		0.38
MutPred		0.60		Loss of MoRF binding (P = 0.0399)
MVP		0.74
MPC		0.88
ClinPred		0.61	D
GERP RS		2.8
Varity_R		0.21
gMVP		0.90
Mutation Taster		=89/11	polymorphism

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: rs79599913; hg19: chr1-203134421;