NM_003886.3:c.1209T>A

Variant names:

• chrX-50193504-A-T
• rs1469104391
• NM_003886.3:c.1209T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003886.3(AKAP4):​c.1209T>A​(p.Phe403Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AKAP4 NM_003886.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.792

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP4	NM_003886.3	c.1209T>A	p.Phe403Leu	missense_variant	Exon 5 of 6	ENST00000358526.7	NP_003877.2
AKAP4	NM_139289.2	c.1182T>A	p.Phe394Leu	missense_variant	Exon 5 of 6		NP_647450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP4	ENST00000358526.7	c.1209T>A	p.Phe403Leu	missense_variant	Exon 5 of 6	1	NM_003886.3	ENSP00000351327.2
AKAP4	ENST00000376064.7	c.1182T>A	p.Phe394Leu	missense_variant	Exon 5 of 6	1		ENSP00000365232.3
AKAP4	ENST00000481402.5	n.1321T>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
AKAP4	ENST00000448865.5	c.542-482T>A		intron_variant	Intron 5 of 5	5		ENSP00000402403.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.83		Loss of catalytic residue at F403 (P = 0.0173);.;
MVP		0.54
MPC		0.68
ClinPred		0.98	D
GERP RS		0.95
Varity_R		0.56
gMVP		0.58

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

Other links and lift over

dbSNP: rs1469104391; hg19: chrX-49958155;