12-4627541-A-T

Position:

• chr12-4627541-A-T

Variant summary

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

The NM_001278309.2(AKAP3):​c.1361T>A​(p.Ile454Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 5.18

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, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP3	NM_001278309.2	c.1361T>A	p.Ile454Asn	missense_variant	5/6	ENST00000228850.6	NP_001265238.2
AKAP3	NM_006422.4	c.1361T>A	p.Ile454Asn	missense_variant	5/6		NP_006413.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP3	ENST00000228850.6	c.1361T>A	p.Ile454Asn	missense_variant	5/6	5	NM_001278309.2	ENSP00000228850.1
ENSG00000272921	ENST00000536588.1	n.142-3781A>T		intron_variant		3		ENSP00000445121.1
AKAP3	ENST00000545990.6	c.1361T>A	p.Ile454Asn	missense_variant	5/6	2		ENSP00000440994.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 78

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

Mar 01, 2023

The c.1361T>A (p.I454N) alteration is located in exon 4 (coding exon 2) of the AKAP3 gene. This alteration results from a T to A substitution at nucleotide position 1361, causing the isoleucine (I) at amino acid position 454 to be replaced by an asparagine (N). 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	0.85
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.68		Loss of stability (P = 0.0301);Loss of stability (P = 0.0301);
MVP		0.67
MPC		0.75
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-4736707;