X-50192620-T-C

Position:

• chrX-50192620-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003886.3(AKAP4):​c.2093A>G​(p.Asp698Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AKAP4 NM_003886.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP4	NM_003886.3	c.2093A>G	p.Asp698Gly	missense_variant	5/6	ENST00000358526.7	NP_003877.2
AKAP4	NM_139289.2	c.2066A>G	p.Asp689Gly	missense_variant	5/6		NP_647450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP4	ENST00000358526.7	c.2093A>G	p.Asp698Gly	missense_variant	5/6	1	NM_003886.3	ENSP00000351327.2
AKAP4	ENST00000376064.7	c.2066A>G	p.Asp689Gly	missense_variant	5/6	1		ENSP00000365232.3
AKAP4	ENST00000481402.5	n.2205A>G		non_coding_transcript_exon_variant	5/6	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.2093A>G (p.D698G) alteration is located in exon 5 (coding exon 5) of the AKAP4 gene. This alteration results from a A to G substitution at nucleotide position 2093, causing the aspartic acid (D) at amino acid position 698 to be replaced by a glycine (G). 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	0.23
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.65
MutPred		0.66		Loss of stability (P = 0.0087);.;
MVP		0.70
MPC		0.72
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.37
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1265383962; hg19: chrX-49957271;