rs144194103

Variant names:

• chrX-50193445-A-G
• rs144194103
• NM_003886.3:c.1268T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003886.3(AKAP4):​c.1268T>C​(p.Met423Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,210,381 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000034 (0 hom. 11 hem.)
• Consequence: AKAP4 NM_003886.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

Genes affected

AKAP4 (HGNC:374): (A-kinase anchoring protein 4) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is localized to the sperm flagellum and may be involved in the regulation of sperm motility. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.102804035).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP4	NM_003886.3	c.1268T>C	p.Met423Thr	missense_variant	Exon 5 of 6	ENST00000358526.7	NP_003877.2
AKAP4	NM_139289.2	c.1241T>C	p.Met414Thr	missense_variant	Exon 5 of 6		NP_647450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP4	ENST00000358526.7	c.1268T>C	p.Met423Thr	missense_variant	Exon 5 of 6	1	NM_003886.3	ENSP00000351327.2
AKAP4	ENST00000376064.7	c.1241T>C	p.Met414Thr	missense_variant	Exon 5 of 6	1		ENSP00000365232.3
AKAP4	ENST00000481402.5	n.1380T>C		non_coding_transcript_exon_variant	Exon 5 of 6	1
AKAP4	ENST00000448865.5	c.542-423T>C		intron_variant	Intron 5 of 5	5		ENSP00000402403.1

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 24 AN: 112249 Hom.: 0 Cov.: 22 AF XY: 0.0000581 AC XY: 2 AN XY: 34407

Gnomad AFR AF: 0.000745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000942

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000767 AC: 14 AN: 182524 Hom.: 0 AF XY: 0.0000297 AC XY: 2 AN XY: 67232

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000337 AC: 37 AN: 1098132 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 11 AN XY: 363498

Gnomad4 AFR exome AF: 0.000644

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000214 AC: 24 AN: 112249 Hom.: 0 Cov.: 22 AF XY: 0.0000581 AC XY: 2 AN XY: 34407

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.0000942

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000712 Hom.: 2

Bravo AF: 0.000212

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1268T>C (p.M423T) alteration is located in exon 5 (coding exon 5) of the AKAP4 gene. This alteration results from a T to C substitution at nucleotide position 1268, causing the methionine (M) at amino acid position 423 to be replaced by a threonine (T). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T;.
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.0010	B;.
Vest4		0.51
MVP		0.19
MPC		0.67
ClinPred		0.056	T
GERP RS		3.4
Varity_R		0.25
gMVP		0.61

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: rs144194103; hg19: chrX-49958096;