17-57105591-G-A

Variant names:

• chr17-57105591-G-A
• rs780178684
• NM_003488.4:c.127G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003488.4(AKAP1):​c.127G>A​(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: AKAP1 NM_003488.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

AKAP1 (HGNC:367): (A-kinase anchoring protein 1) 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 binds to type I and type II regulatory subunits of PKA and anchors them to the mitochondrion. This protein is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07439709).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP1	NM_003488.4	c.127G>A	p.Ala43Thr	missense_variant	Exon 2 of 11	ENST00000337714.8	NP_003479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP1	ENST00000337714.8	c.127G>A	p.Ala43Thr	missense_variant	Exon 2 of 11	1	NM_003488.4	ENSP00000337736.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251294 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461874 Hom.: 0 Cov.: 79 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127G>A (p.A43T) alteration is located in exon 3 (coding exon 1) of the AKAP1 gene. This alteration results from a G to A substitution at nucleotide position 127, causing the alanine (A) at amino acid position 43 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	0.077
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;T;T;T;.;.;.;T;T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	T;.;.;T;T;T;T;.;.;T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.074	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;L;L;.;.;.;L;L;.;L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.33	.;N;.;.;.;.;.;.;N;.;N;.
REVEL	Benign	0.016
Sift	Benign	0.54	.;T;.;.;.;.;.;.;T;.;T;.
Sift4G	Benign	0.14	T;T;T;T;D;T;T;T;T;T;T;T
Polyphen		0.051	.;B;B;B;.;.;.;B;B;.;.;.
Vest4		0.098, 0.091, 0.094, 0.10
MutPred		0.24		Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);Gain of glycosylation at A43 (P = 0.018);
MVP		0.36
MPC		0.26
ClinPred		0.19	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.028
gMVP		0.26

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: rs780178684; hg19: chr17-55182952;