Genetic Variant NM_003886.3:c.1286G>A (chrX-50193427-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_003886.3(AKAP4):c.1286G>A(p.Arg429His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,210,269 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00021 ( 0 hom. 75 hem. )

Consequence

AKAP4
NM_003886.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.90

Publications

1 publications found

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:

ENSG00000301433 (HGNC:):

ENSG00000301433 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40419197).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003886.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP4	NM_003886.3	MANE Select	c.1286G>A	p.Arg429His	missense	Exon 5 of 6	NP_003877.2
	AKAP4	NM_139289.2		c.1259G>A	p.Arg420His	missense	Exon 5 of 6	NP_647450.1	Q5JQC9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKAP4	ENST00000358526.7	TSL:1 MANE Select	c.1286G>A	p.Arg429His	missense	Exon 5 of 6	ENSP00000351327.2	Q5JQC9-1
AKAP4	ENST00000376064.7	TSL:1	c.1259G>A	p.Arg420His	missense	Exon 5 of 6	ENSP00000365232.3	Q5JQC9-2
AKAP4	ENST00000481402.5	TSL:1	n.1398G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

112193

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000244

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

182348

AF XY:

0.0000894

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000633

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000212

AC:

233

AN:

1098076

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

363452

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26401

American (AMR)

AF:

0.0000568

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.0000495

AC:

AN:

40419

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000253

AC:

213

AN:

842105

Other (OTH)

AF:

0.000174

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000134

AC:

AN:

112193

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34353

show subpopulations

African (AFR)

AF:

0.0000649

AC:

AN:

30827

American (AMR)

AF:

0.00

AC:

AN:

10619

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000244

AC:

AN:

53249

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.76

M_CAP

Benign

0.022

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

PhyloP100

2.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

REVEL

Benign

0.23

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.51

MVP

0.73

MPC

0.70

ClinPred

0.13

GERP RS

4.6

Varity_R

0.14

gMVP

0.46

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over