NM_000476.3:c.491A>G

Variant names:

• chr9-127868346-T-C
• rs137853203
• NM_000476.3:c.491A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000476.3(AK1):​c.491A>G​(p.Tyr164Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AK1 NM_000476.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57
• Publications: 9 publications found

Genes affected

AK1 (HGNC:361): (adenylate kinase 1) This gene encodes an adenylate kinase enzyme involved in energy metabolism and homeostasis of cellular adenine nucleotide ratios in different intracellular compartments. This gene is highly expressed in skeletal muscle, brain and erythrocytes. Certain mutations in this gene resulting in a functionally inadequate enzyme are associated with a rare genetic disorder causing nonspherocytic hemolytic anemia. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene shares readthrough transcripts with the upstream ST6GALNAC6 gene. [provided by RefSeq, Jan 2022]

AK1 Gene-Disease associations (from GenCC):

• hemolytic anemia due to adenylate kinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000257524 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 9-127868346-T-C is Pathogenic according to our data. Variant chr9-127868346-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18265.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	NM_000476.3	MANE Select	c.491A>G	p.Tyr164Cys	missense	Exon 6 of 7	NP_000467.1
	AK1	NM_001318122.2		c.539A>G	p.Tyr180Cys	missense	Exon 5 of 6	NP_001305051.1
	AK1	NM_001318121.1		c.491A>G	p.Tyr164Cys	missense	Exon 6 of 7	NP_001305050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	ENST00000644144.2	MANE Select	c.491A>G	p.Tyr164Cys	missense	Exon 6 of 7	ENSP00000494600.1
	ENSG00000257524	ENST00000646171.1		n.*524A>G		non_coding_transcript_exon	Exon 12 of 13	ENSP00000495484.1
	ENSG00000257524	ENST00000646171.1		n.*524A>G		3_prime_UTR	Exon 12 of 13	ENSP00000495484.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000427 AC: 1 AN: 233980 AF XY: 0.00000791

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000103

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: 6.89e-7 AC: 1 AN: 1452070 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721320

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 43242

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.00 AC: 0 AN: 84670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5376

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107528

Other (OTH) AF: 0.00 AC: 0 AN: 59966

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemolytic anemia due to adenylate kinase deficiency Pathogenic:1

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.98		Loss of MoRF binding (P = 0.0925)
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: 1

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

Other links and lift over

dbSNP: rs137853203; hg19: chr9-130630625; COSMIC: COSV99802350; COSMIC: COSV99802350;