Variant 9-132792775-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 made for transcript

Verdict is Likely_pathogenic. Variant got 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/exons	MANE	UniProt
AK8	NM_152572.3 linkuse as main transcript	c.980T>C	p.Val327Ala	missense_variant, splice_region_variant	11/13	ENST00000298545.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK8	ENST00000298545.4 linkuse as main transcript	c.980T>C	p.Val327Ala	missense_variant, splice_region_variant	11/13	1	NM_152572.3	P1	Q96MA6-1
AK8	ENST00000476719.1 linkuse as main transcript	n.1417T>C		splice_region_variant, non_coding_transcript_exon_variant	10/12	5
AK8	ENST00000477396.5 linkuse as main transcript	n.1895T>C		splice_region_variant, non_coding_transcript_exon_variant	13/15	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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000259

Gnomad4 OTH exome

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

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

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

MutationTaster

Benign

1.0

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

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over