17-47975203-C-A

Variant names:

• chr17-47975203-C-A
• rs776945659
• NM_176096.3:c.379C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_176096.3(CDK5RAP3):​c.379C>A​(p.Pro127Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P127A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK5RAP3 NM_176096.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40
• Publications: 0 publications found

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]

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176096.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP3	NM_176096.3	MANE Select	c.379C>A	p.Pro127Thr	missense	Exon 6 of 14	NP_788276.1	Q96JB5-1
	CDK5RAP3	NM_001278197.2		c.454C>A	p.Pro152Thr	missense	Exon 6 of 14	NP_001265126.1	Q96JB5-4
	CDK5RAP3	NM_001278217.2		c.118C>A	p.Pro40Thr	missense	Exon 5 of 13	NP_001265146.1	Q96JB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP3	ENST00000338399.9	TSL:1 MANE Select	c.379C>A	p.Pro127Thr	missense	Exon 6 of 14	ENSP00000344683.4	Q96JB5-1
	CDK5RAP3	ENST00000580287.5	TSL:1	n.1109C>A		non_coding_transcript_exon	Exon 5 of 13
	CDK5RAP3	ENST00000584063.5	TSL:1	n.1132C>A		non_coding_transcript_exon	Exon 5 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.98
MPC		0.79
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776945659; hg19: chr17-46052569;