Genetic Variant AK8:p.Asp344Gly (chr9-132792724-T-C) – 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.1031A>G(p.Asp344Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000213 in 1,405,396 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: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

AK8
NM_152572.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

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, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK8	NM_152572.3 link	c.1031A>G	p.Asp344Gly	missense_variant	Exon 11 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.1031A>G	p.Asp344Gly	missense_variant	Exon 11 of 13	1	NM_152572.3	ENSP00000298545.3	Q96MA6-1
AK8	ENST00000476719.1 link	n.1468A>G		non_coding_transcript_exon_variant	Exon 10 of 12	5
AK8	ENST00000477396.5 link	n.1946A>G		non_coding_transcript_exon_variant	Exon 13 of 15	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1405396

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

693852

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32000

American (AMR)

AF:

0.00

AC:

AN:

36634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25234

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36392

South Asian (SAS)

AF:

0.00

AC:

AN:

79484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4644

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083028

Other (OTH)

AF:

0.0000344

AC:

AN:

58174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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

Mar 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1031A>G (p.D344G) alteration is located in exon 11 (coding exon 11) of the AK8 gene. This alteration results from a A to G substitution at nucleotide position 1031, causing the aspartic acid (D) at amino acid position 344 to be replaced by a glycine (G). 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

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

3.4

PhyloP100

5.2

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0040

Polyphen

0.69

Vest4

0.89

MutPred

0.71

Loss of ubiquitination at K348 (P = 0.0653);

MVP

0.64

MPC

0.51

ClinPred

0.99

GERP RS

5.2

Varity_R

0.69

gMVP

0.73

Mutation Taster

=96/4

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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9-132792724-T-C

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