Genetic Variant AK8:p.Val327Ala (chr9-132792775-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152572.3(AK8):c.980T>C(p.Val327Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000199 in 1,406,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

AK8
NM_152572.3 missense, splice_region

Scores

Splicing: ADA: 0.01155

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.07

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK8	NM_152572.3 link	c.980T>C	p.Val327Ala	missense_variant, splice_region_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.980T>C	p.Val327Ala	missense_variant, splice_region_variant	Exon 11 of 13	1	NM_152572.3	ENSP00000298545.3	Q96MA6-1
AK8	ENST00000476719.1 link	n.1417T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 12	5
AK8	ENST00000477396.5 link	n.1895T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 15	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1406112

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

694018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32060

American (AMR)

AF:

0.00

AC:

AN:

36796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25212

East Asian (EAS)

AF:

0.00

AC:

AN:

36446

South Asian (SAS)

AF:

0.00

AC:

AN:

79414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5146

European-Non Finnish (NFE)

AF:

0.0000259

AC:

AN:

1082974

Other (OTH)

AF:

0.00

AC:

AN:

58248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

Jun 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.980T>C (p.V327A) alteration is located in exon 11 (coding exon 11) of the AK8 gene. This alteration results from a T to C substitution at nucleotide position 980, causing the valine (V) at amino acid position 327 to be replaced by an alanine (A). 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

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.4

PhyloP100

6.1

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.74

Sift

Benign

0.063

Sift4G

Benign

0.073

Polyphen

0.036

Vest4

0.81

MutPred

0.92

Gain of disorder (P = 0.0452);

MVP

0.81

MPC

0.15

ClinPred

0.94

GERP RS

5.2

Varity_R

0.21

gMVP

0.69

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.038

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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9-132792775-A-G

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