12-4627365-G-A

Position:

• chr12-4627365-G-A

Variant summary

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

The NM_001278309.2(AKAP3):​c.1537C>T​(p.Pro513Ser) 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 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)
• Consequence: AKAP3 NM_001278309.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.217

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]

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=0.057113618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP3	NM_001278309.2	c.1537C>T	p.Pro513Ser	missense_variant	5/6	ENST00000228850.6	NP_001265238.2
AKAP3	NM_006422.4	c.1537C>T	p.Pro513Ser	missense_variant	5/6		NP_006413.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP3	ENST00000228850.6	c.1537C>T	p.Pro513Ser	missense_variant	5/6	5	NM_001278309.2	ENSP00000228850	P1
AKAP3	ENST00000545990.6	c.1537C>T	p.Pro513Ser	missense_variant	5/6	2		ENSP00000440994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 77

GnomAD4 genome Cov.: 32

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

Jan 23, 2023

The c.1537C>T (p.P513S) alteration is located in exon 4 (coding exon 2) of the AKAP3 gene. This alteration results from a C to T substitution at nucleotide position 1537, causing the proline (P) at amino acid position 513 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.9
DANN	Benign	0.82
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.063
Sift	Benign	0.57	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.13	B;B
Vest4		0.14
MutPred		0.41		Gain of phosphorylation at P513 (P = 0.0441);Gain of phosphorylation at P513 (P = 0.0441);
MVP		0.28
MPC		0.23
ClinPred		0.071	T
GERP RS		-1.4
Varity_R		0.023
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-4736531;