17-47973629-G-A

Position:

• chr17-47973629-G-A

Variant summary

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

The NM_176096.3(CDK5RAP3):​c.163G>A​(p.Ala55Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDK5RAP3 NM_176096.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

Genes affected

CDK5RAP3 (HGNC:18673): (CDK5 regulatory subunit associated protein 3) This gene encodes a protein that has been reported to function in signaling pathways governing transcriptional regulation and cell cycle progression. It may play a role in tumorigenesis and metastasis. A pseudogene of this gene is located on the long arm of chromosome 20. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, May 2013]

CDK5RAP3 (HGNC:):

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=0.16845694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5RAP3	NM_176096.3	c.163G>A	p.Ala55Thr	missense_variant	3/14	ENST00000338399.9	NP_788276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5RAP3	ENST00000338399.9	c.163G>A	p.Ala55Thr	missense_variant	3/14	1	NM_176096.3	ENSP00000344683.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727202

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Nov 09, 2024

The c.163G>A (p.A55T) alteration is located in exon 3 (coding exon 3) of the CDK5RAP3 gene. This alteration results from a G to A substitution at nucleotide position 163, causing the alanine (A) at amino acid position 55 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	Benign	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0075	.;.;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T;T;T;D;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	.;.;N;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.42	.;N;N;.;.
REVEL	Benign	0.022
Sift	Benign	0.43	.;T;T;.;.
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.056	.;.;B;.;.
Vest4		0.15, 0.15
MutPred		0.36		.;.;Gain of disorder (P = 0.1355);.;Gain of disorder (P = 0.1355);
MVP		0.57
MPC		0.18
ClinPred		0.54	D
GERP RS		4.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.043
gMVP		0.11

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: rs1490985530; hg19: chr17-46050995; COSMIC: COSV58114979; COSMIC: COSV58114979;