12-4627487-A-G

Position:

• chr12-4627487-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001278309.2(AKAP3):​c.1415T>C​(p.Leu472Pro) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKAP3 NM_001278309.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.32

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03443402).
• BP6: Variant 12-4627487-A-G is Benign according to our data. Variant chr12-4627487-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2375097.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP3	NM_001278309.2	c.1415T>C	p.Leu472Pro	missense_variant	5/6	ENST00000228850.6	NP_001265238.2
AKAP3	NM_006422.4	c.1415T>C	p.Leu472Pro	missense_variant	5/6		NP_006413.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP3	ENST00000228850.6	c.1415T>C	p.Leu472Pro	missense_variant	5/6	5	NM_001278309.2	ENSP00000228850.1
ENSG00000272921	ENST00000536588.1	n.142-3835A>G		intron_variant		3		ENSP00000445121.1
AKAP3	ENST00000545990.6	c.1415T>C	p.Leu472Pro	missense_variant	5/6	2		ENSP00000440994.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.0043	T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.39	.;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.7	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.68	N;N
REVEL	Benign	0.067
Sift	Benign	0.84	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	B;B
Vest4		0.051
MutPred		0.48		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP		0.18
MPC		0.20
ClinPred		0.041	T
GERP RS		4.8
Varity_R		0.079
gMVP		0.053

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr12-4736653;