9-127868063-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting

The NM_000476.3(AK1):c.530G>A(p.Gly177Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000379 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G177V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

AK1
NM_000476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.61

Publications

4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

AK1 links:

ENSG00000257524 (HGNC:):

ENSG00000257524 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity KAD1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.2518608).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000289 (44/152284) while in subpopulation NFE AF = 0.000441 (30/68026). AF 95% confidence interval is 0.000317. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AK1	NM_000476.3	MANE Select	c.530G>A	p.Gly177Asp	missense	Exon 7 of 7	NP_000467.1	P00568
AK1	NM_001318122.2		c.578G>A	p.Gly193Asp	missense	Exon 6 of 6	NP_001305051.1	Q5T9B7
AK1	NM_001318121.1		c.530G>A	p.Gly177Asp	missense	Exon 7 of 7	NP_001305050.1	Q6FGX9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AK1	ENST00000644144.2	MANE Select	c.530G>A	p.Gly177Asp	missense	Exon 7 of 7	ENSP00000494600.1	P00568
ENSG00000257524	ENST00000646171.1		n.*563G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000495484.1	A0A2R8YFX0
ENSG00000257524	ENST00000646171.1		n.*563G>A		3_prime_UTR	Exon 13 of 13	ENSP00000495484.1	A0A2R8YFX0

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000249

AC:

AN:

249166

AF XY:

0.000289

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000466

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000388

AC:

567

AN:

1461806

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

274

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.0000894

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000478

AC:

532

AN:

1111958

Other (OTH)

AF:

0.000315

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000289

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41556

American (AMR)

AF:

0.000392

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000426

Hom.:

Bravo

AF:

0.000249

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hemolytic anemia due to adenylate kinase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.052

MetaRNN

Benign

0.25

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.5

PhyloP100

4.6

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.33

Sift

Benign

0.092

Sift4G

Benign

0.45

Polyphen

0.80

Vest4

0.43

MVP

0.38

MPC

1.0

ClinPred

0.51

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.67

Mutation Taster

=49/51

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over