rs35902264

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000476.3(AK1):c.484G>A(p.Ala162Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,606,966 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A162G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0075 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 57 hom. )

Consequence

AK1
NM_000476.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.104

Publications

6 publications found

Variant links:

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

AK1 links:

ENSG00000257524 (HGNC:):

ENSG00000257524 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005394697).

BP6

Variant 9-127868353-C-T is Benign according to our data. Variant chr9-127868353-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00751 (1144/152300) while in subpopulation SAS AF = 0.0274 (132/4822). AF 95% confidence interval is 0.0236. There are 17 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK1	NM_000476.3 link	c.484G>A	p.Ala162Thr	missense_variant	Exon 6 of 7	ENST00000644144.2	NP_000467.1	P00568Q6FGX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK1	ENST00000644144.2 link	c.484G>A	p.Ala162Thr	missense_variant	Exon 6 of 7	NM_000476.3	ENSP00000494600.1	P00568
ENSG00000257524	ENST00000646171.1 link	n.*517G>A		non_coding_transcript_exon_variant	Exon 12 of 13		ENSP00000495484.1	A0A2R8YFX0
ENSG00000257524	ENST00000646171.1 link	n.*517G>A		3_prime_UTR_variant	Exon 12 of 13		ENSP00000495484.1	A0A2R8YFX0

Frequencies

GnomAD3 genomes

AF:

0.00752

AC:

1144

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00506

AC:

1207

AN:

238538

AF XY:

0.00564

show subpopulations

Gnomad AFR exome

AF:

0.0233

Gnomad AMR exome

AF:

0.000780

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00300

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000838

Gnomad OTH exome

AF:

0.00321

GnomAD4 exome

AF:

0.00220

AC:

3207

AN:

1454666

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

1997

AN XY:

722880

show subpopulations

African (AFR)

AF:

0.0227

AC:

759

AN:

33388

American (AMR)

AF:

0.000915

AC:

AN:

43704

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25978

East Asian (EAS)

AF:

0.00144

AC:

AN:

39518

South Asian (SAS)

AF:

0.0247

AC:

2098

AN:

84996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52706

Middle Eastern (MID)

AF:

0.00293

AC:

AN:

5452

European-Non Finnish (NFE)

AF:

0.0000343

AC:

AN:

1108814

Other (OTH)

AF:

0.00329

AC:

198

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

248

496

743

991

1239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00751

AC:

1144

AN:

152300

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0229

AC:

953

AN:

41560

American (AMR)

AF:

0.00163

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00270

AC:

AN:

5182

South Asian (SAS)

AF:

0.0274

AC:

132

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68020

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00742

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00569

AC:

691

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hemolytic anemia due to adenylate kinase deficiency

Benign:1

Mar 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

2.4

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.32

T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.75

.;.;T;T

MetaRNN

Benign

0.0054

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L;.

PhyloP100

0.10

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.54

N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.51

T;.;T;T

Sift4G

Benign

0.57

T;.;T;T

Polyphen

0.017

B;B;B;.

Vest4

0.079

MVP

0.58

MPC

0.29

ClinPred

0.0020

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.36

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over