Genetic Variant NM_152572.3:c.1421T>A (chr9-132725707-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152572.3(AK8):c.1421T>A(p.Leu474Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,424,750 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

AK8
NM_152572.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.67

Publications

0 publications found

Variant links:

Genes affected

AK8 (HGNC:26526): (adenylate kinase 8) Enables AMP binding activity and nucleobase-containing compound kinase activity. Involved in nucleoside diphosphate phosphorylation and nucleoside triphosphate biosynthetic process. Located in 9+2 motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

AK8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK8	NM_152572.3 link	c.1421T>A	p.Leu474Gln	missense_variant	Exon 13 of 13	ENST00000298545.4	NP_689785.1	Q96MA6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AK8	ENST00000298545.4 link	c.1421T>A	p.Leu474Gln	missense_variant	Exon 13 of 13	1	NM_152572.3	ENSP00000298545.3	Q96MA6-1
AK8	ENST00000467161.1 link	n.364T>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
AK8	ENST00000476719.1 link	n.1858T>A		non_coding_transcript_exon_variant	Exon 12 of 12	5
AK8	ENST00000477396.5 link	n.2336T>A		non_coding_transcript_exon_variant	Exon 15 of 15	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000484

AC:

AN:

206776

AF XY:

0.00000910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

7.02e-7

AC:

AN:

1424750

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33188

American (AMR)

AF:

0.00

AC:

AN:

38890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.00

AC:

AN:

38712

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51646

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090660

Other (OTH)

AF:

0.00

AC:

AN:

59060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1421T>A (p.L474Q) alteration is located in exon 13 (coding exon 13) of the AK8 gene. This alteration results from a T to A substitution at nucleotide position 1421, causing the leucine (L) at amino acid position 474 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

2.9

PhyloP100

6.7

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.87

MutPred

0.63

Loss of catalytic residue at L474 (P = 0.0122);

MVP

0.79

MPC

0.53

ClinPred

0.99

GERP RS

5.1

Varity_R

0.71

gMVP

0.55

Mutation Taster

=97/3

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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NM_152572.3:c.1421T>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over