NM_001278309.2:c.1922A>T

Variant names:

• chr12-4626980-T-A
• rs138981206
• NM_001278309.2:c.1922A>T

Variant summary

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

The NM_001278309.2(AKAP3):​c.1922A>T​(p.Tyr641Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,614,032 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: AKAP3 NM_001278309.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0250

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027320445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP3	NM_001278309.2	c.1922A>T	p.Tyr641Phe	missense_variant	Exon 5 of 6	ENST00000228850.6	NP_001265238.2
AKAP3	NM_006422.4	c.1922A>T	p.Tyr641Phe	missense_variant	Exon 5 of 6		NP_006413.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP3	ENST00000228850.6	c.1922A>T	p.Tyr641Phe	missense_variant	Exon 5 of 6	5	NM_001278309.2	ENSP00000228850.1
ENSG00000272921	ENST00000536588.1	n.142-4342T>A		intron_variant	Intron 1 of 6	3		ENSP00000445121.1
AKAP3	ENST00000545990.6	c.1922A>T	p.Tyr641Phe	missense_variant	Exon 5 of 6	2		ENSP00000440994.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000343 AC: 86 AN: 250908 Hom.: 1 AF XY: 0.000310 AC XY: 42 AN XY: 135596

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000174

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: 0.000644

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000696 AC: 1018 AN: 1461860 Hom.: 0 Cov.: 75 AF XY: 0.000628 AC XY: 457 AN XY: 727232

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000134

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: 0.000878

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74342

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.00120

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1922A>T (p.Y641F) alteration is located in exon 4 (coding exon 2) of the AKAP3 gene. This alteration results from a A to T substitution at nucleotide position 1922, causing the tyrosine (Y) at amino acid position 641 to be replaced by a phenylalanine (F). 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	0.093
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.48
DEOGEN2	Benign	0.0055	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.50	N;N
REVEL	Benign	0.024
Sift	Benign	0.69	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.079	B;B
Vest4		0.067
MVP		0.29
MPC		0.17
ClinPred		0.0097	T
GERP RS		0.65
Varity_R		0.040
gMVP		0.041

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: rs138981206; hg19: chr12-4736146;