Genetic Variant AKAP4:p.Ile270Thr (chrX-50193904-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003886.3(AKAP4):c.809T>C(p.Ile270Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000546 in 1,210,223 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 221 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 0.00023 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00058 ( 0 hom. 217 hem. )

Consequence

AKAP4
NM_003886.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23969135).

BS2

High Hemizygotes in GnomAd4 at 4 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.809T>C	p.Ile270Thr	missense	Exon 5 of 6	NP_003877.2
	AKAP4	NM_139289.2		c.782T>C	p.Ile261Thr	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.809T>C	p.Ile270Thr	missense	Exon 5 of 6	ENSP00000351327.2	Q5JQC9-1
AKAP4	ENST00000376064.7	TSL:1	c.782T>C	p.Ile261Thr	missense	Exon 5 of 6	ENSP00000365232.3	Q5JQC9-2
AKAP4	ENST00000481402.5	TSL:1	n.921T>C		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

112116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

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:

0.000395

Gnomad OTH

AF:

0.000664

GnomAD2 exomes

AF:

0.000295

AC:

AN:

182911

AF XY:

0.000326

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000661

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000578

AC:

635

AN:

1098107

Hom.:

Cov.:

AF XY:

0.000597

AC XY:

217

AN XY:

363481

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000740

AC:

623

AN:

842106

Other (OTH)

AF:

0.000260

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000232

AC:

AN:

112116

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34276

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30871

American (AMR)

AF:

0.00

AC:

AN:

10590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6123

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000395

AC:

AN:

53198

Other (OTH)

AF:

0.000664

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000276

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.68

M_CAP

Benign

0.017

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

PhyloP100

3.7

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.1

REVEL

Benign

0.27

Sift

Uncertain

0.0040

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.66

MVP

0.44

MPC

0.70

ClinPred

0.22

GERP RS

4.9

Varity_R

0.18

gMVP

0.25

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