chr22-24441001-A-T

Position:

• chr22-24441001-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000675.6(ADORA2A):​c.751A>T​(p.Ile251Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADORA2A NM_000675.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

ADORA2A (HGNC:263): (adenosine A2a receptor) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) superfamily, which is subdivided into classes and subtypes. The receptors are seven-pass transmembrane proteins that respond to extracellular cues and activate intracellular signal transduction pathways. This protein, an adenosine receptor of A2A subtype, uses adenosine as the preferred endogenous agonist and preferentially interacts with the G(s) and G(olf) family of G proteins to increase intracellular cAMP levels. It plays an important role in many biological functions, such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders. Alternative splicing results in multiple transcript variants. A read-through transcript composed of the upstream SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

SPECC1L-ADORA2A (HGNC:):

ADORA2A-AS1 (HGNC:37122): (ADORA2A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.751A>T	p.Ile251Phe	missense_variant	3/3	ENST00000337539.12	NP_000666.2
SPECC1L-ADORA2A	NR_103546.1	n.4930A>T		non_coding_transcript_exon_variant	20/20
ADORA2A-AS1	NR_028484.3	n.833+991T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.751A>T	p.Ile251Phe	missense_variant	3/3	1	NM_000675.6	ENSP00000336630	P1
ADORA2A-AS1	ENST00000326341.8	n.559+991T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

The c.751A>T (p.I251F) alteration is located in exon 3 (coding exon 2) of the ADORA2A gene. This alteration results from a A to T substitution at nucleotide position 751, causing the isoleucine (I) at amino acid position 251 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;.;D;D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;.;.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	.;D;D;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	.;D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.96	D;.;D;D;D
Vest4		0.66
MutPred		0.58		Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);
MVP		0.87
MPC		1.6
ClinPred		0.94	D
GERP RS		1.8
Varity_R		0.70
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24836969;