rs786205458

Variant names:

• chr10-74589296-T-A
• rs786205458
• NM_006721.4:c.741T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006721.4(ADK):​c.741T>A​(p.Phe247Leu) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADK NM_006721.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.86
• Publications: 2 publications found

Genes affected

ADK (HGNC:257): (adenosine kinase) This gene an enzyme which catalyzes the transfer of the gamma-phosphate from ATP to adenosine, thereby serving as a regulator of concentrations of both extracellular adenosine and intracellular adenine nucleotides. Adenosine has widespread effects on the cardiovascular, nervous, respiratory, and immune systems and inhibitors of the enzyme could play an important pharmacological role in increasing intravascular adenosine concentrations and acting as anti-inflammatory agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ADK Gene-Disease associations (from GenCC):

• adenosine kinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

LOC124902457 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-74589296-T-A is Pathogenic according to our data. Variant chr10-74589296-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191003.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006721.4. 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
	ADK	NM_006721.4	MANE Select	c.741T>A	p.Phe247Leu	missense	Exon 8 of 11	NP_006712.2
	ADK	NM_001123.4		c.690T>A	p.Phe230Leu	missense	Exon 8 of 11	NP_001114.2
	ADK	NM_001202449.2		c.636T>A	p.Phe212Leu	missense	Exon 7 of 10	NP_001189378.1	P55263-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADK	ENST00000539909.6	TSL:2 MANE Select	c.741T>A	p.Phe247Leu	missense	Exon 8 of 11	ENSP00000443965.2	P55263-1
	ADK	ENST00000286621.7	TSL:1	c.741T>A	p.Phe247Leu	missense	Exon 8 of 12	ENSP00000286621.3	A0A5K1VW54
	ADK	ENST00000372734.5	TSL:1	c.690T>A	p.Phe230Leu	missense	Exon 8 of 11	ENSP00000361819.3	P55263-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Adenosine kinase deficiency (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.55
Sift	Benign	0.18	T
Sift4G	Benign	0.23	T
Polyphen		0.51	P
Vest4		0.60
MutPred		0.58		Gain of disorder (P = 0.2048)
MVP		0.87
MPC		0.68
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.80
gMVP		0.82
Mutation Taster		=0/100	disease causing

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: rs786205458; hg19: chr10-76349054;