X-50192509-T-C

Variant names:

• chrX-50192509-T-C
• rs61751433
• NM_003886.3:c.2204A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003886.3(AKAP4):​c.2204A>G​(p.Asn735Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,799 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: AKAP4 NM_003886.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07719213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP4	NM_003886.3	c.2204A>G	p.Asn735Ser	missense_variant	Exon 5 of 6	ENST00000358526.7	NP_003877.2
AKAP4	NM_139289.2	c.2177A>G	p.Asn726Ser	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.2204A>G	p.Asn735Ser	missense_variant	Exon 5 of 6	1	NM_003886.3	ENSP00000351327.2
AKAP4	ENST00000376064.7	c.2177A>G	p.Asn726Ser	missense_variant	Exon 5 of 6	1		ENSP00000365232.3
AKAP4	ENST00000481402.5	n.2316A>G		non_coding_transcript_exon_variant	Exon 5 of 6	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097799 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363185

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.24
DANN	Benign	0.17
DEOGEN2	Benign	0.046	T;.
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	M;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.50	N;N
REVEL	Benign	0.049
Sift	Benign	0.52	T;T
Sift4G	Benign	0.91	T;T
Polyphen		0.043	B;.
Vest4		0.051
MutPred		0.28		Gain of glycosylation at N735 (P = 0.0736);.;
MVP		0.45
MPC		0.11
ClinPred		0.054	T
GERP RS		1.6
Varity_R		0.028
gMVP		0.14

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: rs61751433; hg19: chrX-49957160;