chrX-50193224-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_003886.3(AKAP4):c.1489G>A(p.Gly497Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,209,833 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000051 ( 0 hom. 18 hem. )

Consequence

AKAP4
NM_003886.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.42

Variant links:

Genes affected

AKAP4 (HGNC:374): (A-kinase anchoring protein 4) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is localized to the sperm flagellum and may be involved in the regulation of sperm motility. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

AKAP4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07558912).

BP6

Variant X-50193224-C-T is Benign according to our data. Variant chrX-50193224-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3515031.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP4	NM_003886.3 link	c.1489G>A	p.Gly497Ser	missense_variant	Exon 5 of 6	ENST00000358526.7	NP_003877.2	Q5JQC9-1A0A384MQY7
AKAP4	NM_139289.2 link	c.1462G>A	p.Gly488Ser	missense_variant	Exon 5 of 6		NP_647450.1	Q5JQC9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AKAP4	ENST00000358526.7 link	c.1489G>A	p.Gly497Ser	missense_variant	Exon 5 of 6	1	NM_003886.3	ENSP00000351327.2	Q5JQC9-1
AKAP4	ENST00000376064.7 link	c.1462G>A	p.Gly488Ser	missense_variant	Exon 5 of 6	1		ENSP00000365232.3	Q5JQC9-2
AKAP4	ENST00000481402.5 link	n.1601G>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
AKAP4	ENST00000448865.5 link	c.542-202G>A		intron_variant	Intron 5 of 5	5		ENSP00000402403.1	A0A075B6Q6

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111863

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34033

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

182667

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67321

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000737

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1097970

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

363342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000653

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111863

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34033

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 11, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0040

DANN

Benign

0.58

DEOGEN2

Benign

0.063

T;.

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.076

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.65

N;N

REVEL

Benign

0.065

Sift

Benign

0.35

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.56

P;.

Vest4

0.077

MutPred

0.64

Gain of phosphorylation at G497 (P = 0.0677);.;

MVP

0.40

MPC

0.17

ClinPred

0.041

GERP RS

-4.5

Varity_R

0.069

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over