15-85639419-G-A

Variant names:

• chr15-85639419-G-A
• rs145684674
• NM_007200.5:c.4207G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007200.5(AKAP13):​c.4207G>A​(p.Ala1403Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,460,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: AKAP13 NM_007200.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.918

Genes affected

AKAP13 (HGNC:371): (A-kinase anchoring protein 13) 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. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]

AKAP13-AS1 (HGNC:55975): (AKAP13 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042848945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP13	NM_007200.5	c.4207G>A	p.Ala1403Thr	missense_variant	Exon 9 of 37	ENST00000394518.7	NP_009131.2
AKAP13	NM_006738.6	c.4207G>A	p.Ala1403Thr	missense_variant	Exon 9 of 37		NP_006729.4
AKAP13	NM_001270546.1	c.127G>A	p.Ala43Thr	missense_variant	Exon 2 of 29		NP_001257475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP13	ENST00000394518.7	c.4207G>A	p.Ala1403Thr	missense_variant	Exon 9 of 37	1	NM_007200.5	ENSP00000378026.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250754 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135522

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: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460826 Hom.: 0 Cov.: 29 AF XY: 0.0000316 AC XY: 23 AN XY: 726758

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: 0.0000378

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4207G>A (p.A1403T) alteration is located in exon 9 (coding exon 8) of the AKAP13 gene. This alteration results from a G to A substitution at nucleotide position 4207, causing the alanine (A) at amino acid position 1403 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	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.9
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T;T;.;T;.;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.043	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.75	.;N;N;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.030	N;N;N;.;.;.;.
REVEL	Benign	0.020
Sift	Benign	0.37	T;T;T;.;.;.;.
Sift4G	Benign	0.33	T;T;T;T;T;T;T
Polyphen		0.010, 0.018	.;B;B;.;.;.;.
Vest4		0.098, 0.061, 0.21, 0.20
MVP		0.50
MPC		0.039
ClinPred		0.062	T
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.18

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: rs145684674; hg19: chr15-86182650;