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

Variant summary

Our verdict is Likely benign. Variant got -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. 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

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

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP4	NM_003886.3 link	c.809T>C	p.Ile270Thr	missense_variant	Exon 5 of 6	ENST00000358526.7	NP_003877.2	Q5JQC9-1A0A384MQY7
AKAP4	NM_139289.2 link	c.782T>C	p.Ile261Thr	missense_variant	Exon 5 of 6		NP_647450.1	Q5JQC9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP4	ENST00000358526.7 link	c.809T>C	p.Ile270Thr	missense_variant	Exon 5 of 6	1	NM_003886.3	ENSP00000351327.2		Q5JQC9-1

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

112116

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34276

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

GnomAD3 exomes

AF:

0.000295

AC:

AN:

182911

Hom.:

AF XY:

0.000326

AC XY:

AN XY:

67483

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:

0.000661

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

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:

0.000740

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.000232

AC:

AN:

112116

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34276

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000395

Gnomad4 OTH

AF:

0.000664

Alfa

AF:

0.000300

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.809T>C (p.I270T) alteration is located in exon 5 (coding exon 5) of the AKAP4 gene. This alteration results from a T to C substitution at nucleotide position 809, causing the isoleucine (I) at amino acid position 270 to be replaced by a threonine (T). 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

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.17

T;T

Polyphen

1.0

D;.

Vest4

0.66

MVP

0.44

MPC

0.70

ClinPred

0.22

GERP RS

4.9

Varity_R

0.18

gMVP

0.25

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