12-4615831-C-A

Position:

• chr12-4615831-C-A

Variant summary

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

The NM_001278309.2(AKAP3):​c.2470G>T​(p.Val824Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: AKAP3 NM_001278309.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.10

Genes affected

AKAP3 (HGNC:373): (A-kinase anchoring protein 3) This gene encodes a member of A-kinase anchoring proteins (AKAPs), a family of functionally related proteins that target protein kinase A to discrete locations within the cell. The encoded protein is reported to participate in protein-protein interactions with the R-subunit of the protein kinase A as well as sperm-associated proteins. This protein is expressed in spermatozoa and localized to the acrosomal region of the sperm head as well as the length of the principal piece. It may function as a regulator of motility, capacitation, and the acrosome reaction. [provided by RefSeq, May 2013]

ENSG00000272921 (HGNC:):

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, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP3	NM_001278309.2	c.2470G>T	p.Val824Leu	missense_variant	6/6	ENST00000228850.6	NP_001265238.2
AKAP3	NM_006422.4	c.2470G>T	p.Val824Leu	missense_variant	6/6		NP_006413.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP3	ENST00000228850.6	c.2470G>T	p.Val824Leu	missense_variant	6/6	5	NM_001278309.2	ENSP00000228850.1
ENSG00000272921	ENST00000536588.1	n.141+10745C>A		intron_variant		3		ENSP00000445121.1
AKAP3	ENST00000545990.6	c.2470G>T	p.Val824Leu	missense_variant	6/6	2		ENSP00000440994.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727244

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Apr 17, 2024

The c.2470G>T (p.V824L) alteration is located in exon 5 (coding exon 3) of the AKAP3 gene. This alteration results from a G to T substitution at nucleotide position 2470, causing the valine (V) at amino acid position 824 to be replaced by a leucine (L). 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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.57
MutPred		0.73		Gain of ubiquitination at K829 (P = 0.1215);Gain of ubiquitination at K829 (P = 0.1215);
MVP		0.63
MPC		0.57
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.53

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: rs898234026; hg19: chr12-4724997;