Genetic Variant NM_176096.3:c.703A>T (chr17-47975918-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_176096.3(CDK5RAP3):c.703A>T(p.Asn235Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000656 in 152,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N235D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

CDK5RAP3
NM_176096.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.68

Publications

0 publications found

Variant links:

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 links:

ENSG00000263798 (HGNC:):

ENSG00000263798 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5RAP3	NM_176096.3	MANE Select	c.703A>T	p.Asn235Tyr	missense	Exon 8 of 14	NP_788276.1	Q96JB5-1
CDK5RAP3	NM_001278197.2		c.778A>T	p.Asn260Tyr	missense	Exon 8 of 14	NP_001265126.1	Q96JB5-4
CDK5RAP3	NM_001278217.2		c.442A>T	p.Asn148Tyr	missense	Exon 7 of 13	NP_001265146.1	Q96JB5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5RAP3	ENST00000338399.9	TSL:1 MANE Select	c.703A>T	p.Asn235Tyr	missense	Exon 8 of 14	ENSP00000344683.4	Q96JB5-1
CDK5RAP3	ENST00000580287.5	TSL:1	n.1648A>T		non_coding_transcript_exon	Exon 6 of 13
CDK5RAP3	ENST00000584063.5	TSL:1	n.1671A>T		non_coding_transcript_exon	Exon 6 of 12

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.4

PhyloP100

3.7

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.84

MutPred

0.66

Gain of phosphorylation at N235 (P = 0.0392)

MVP

0.78

MPC

0.80

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over