NM_006721.4:c.21G>C

Variant names:

• chr10-74151299-G-C
• rs971684446
• NM_006721.4:c.21G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006721.4(ADK):​c.21G>C​(p.Glu7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,397,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADK NM_006721.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107
• 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]

AP3M1 (HGNC:569): (adaptor related protein complex 3 subunit mu 1) The protein encoded by this gene is the medium subunit of AP-3, which is an adaptor-related protein complex associated with the Golgi region as well as more peripheral intracellular structures. AP-3 facilitates the budding of vesicles from the Golgi membrane, and it may directly function in protein sorting to the endosomal/lysosomal system. AP-3 is a heterotetrameric protein complex composed of two large subunits (delta and beta3), a medium subunit (mu3), and a small subunit (sigma 3). Mutations in one of the large subunits of AP-3 have been associated with the Hermansky-Pudlak syndrome, a genetic disorder characterized by defective lysosome-related organelles. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15002102).

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.21G>C	p.Glu7Asp	missense	Exon 1 of 11	NP_006712.2
	ADK	NM_001202450.2		c.21G>C	p.Glu7Asp	missense	Exon 1 of 10	NP_001189379.1	P55263-3
	ADK	NM_001369123.1		c.21G>C	p.Glu7Asp	missense	Exon 1 of 10	NP_001356052.1	A0A5F9ZH31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADK	ENST00000539909.6	TSL:2 MANE Select	c.21G>C	p.Glu7Asp	missense	Exon 1 of 11	ENSP00000443965.2	P55263-1
	ADK	ENST00000286621.7	TSL:1	c.21G>C	p.Glu7Asp	missense	Exon 1 of 12	ENSP00000286621.3	A0A5K1VW54
	ADK	ENST00000960305.1		c.21G>C	p.Glu7Asp	missense	Exon 1 of 12	ENSP00000630364.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000192 AC: 3 AN: 156082 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397336 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689178

African (AFR) AF: 0.00 AC: 0 AN: 31530

American (AMR) AF: 0.0000840 AC: 3 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078802

Other (OTH) AF: 0.00 AC: 0 AN: 57818

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.11
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.23
Sift	Benign	0.064	T
Sift4G	Benign	0.25	T
Polyphen		0.53	P
Vest4		0.21
MutPred		0.27		Loss of solvent accessibility (P = 0.0509)
MVP		0.41
MPC		0.25
ClinPred		0.44	T
GERP RS		-2.7
PromoterAI		-0.049	Neutral
Varity_R		0.13
gMVP		0.22
Mutation Taster		=95/5	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: rs971684446; hg19: chr10-75911057;