1-111500226-C-A

Variant names:

• chr1-111500226-C-A
• NM_000677.4:c.681G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000677.4(ADORA3):​c.681G>T​(p.Lys227Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADORA3 NM_000677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37321624).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000677.4. 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
	ADORA3	NM_000677.4	MANE Select	c.681G>T	p.Lys227Asn	missense	Exon 2 of 2	NP_000668.1	P0DMS8-1
	TMIGD3	NM_020683.7	MANE Select	c.350+2779G>T		intron	N/A	NP_065734.5
	ADORA3	NM_001302679.2		c.246G>T	p.Lys82Asn	missense	Exon 2 of 2	NP_001289608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA3	ENST00000241356.5	TSL:1 MANE Select	c.681G>T	p.Lys227Asn	missense	Exon 2 of 2	ENSP00000241356.4	P0DMS8-1
	TMIGD3	ENST00000369716.9	TSL:1 MANE Select	c.350+2779G>T		intron	N/A	ENSP00000358730.4	P0DMS9-2
	TMIGD3	ENST00000369717.8	TSL:1	c.108-9464G>T		intron	N/A	ENSP00000358731.4	P0DMS9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.9
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.061	T
Sift4G	Uncertain	0.047	D
Vest4		0.24
MutPred		0.71		Loss of ubiquitination at K227 (P = 0.0244)
MVP		0.17
ClinPred		0.77	D
GERP RS		4.9
Varity_R		0.46
gMVP		0.51
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr1-112042848;