10-74398467-T-TTGGG

Variant names:

• chr10-74398467-T-TTGGG
• NM_006721.4:c.447-3_447-2insGGGT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006721.4(ADK):​c.447-3_447-2insGGGT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADK NM_006721.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 0 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10009183 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 0 (no position change), new splice context is: tctttggttgttttgggtAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.447-3_447-2insGGGT		splice_acceptor intron	N/A	NP_006712.2
	ADK	NM_001123.4		c.396-3_396-2insGGGT		splice_acceptor intron	N/A	NP_001114.2
	ADK	NM_001202449.2		c.342-3_342-2insGGGT		splice_acceptor intron	N/A	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.447-4_447-3insTGGG		splice_region intron	N/A	ENSP00000443965.2	P55263-1
	ADK	ENST00000286621.7	TSL:1	c.447-4_447-3insTGGG		splice_region intron	N/A	ENSP00000286621.3	A0A5K1VW54
	ADK	ENST00000372734.5	TSL:1	c.396-4_396-3insTGGG		splice_region intron	N/A	ENSP00000361819.3	P55263-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr10-76158225;