Genetic Variant NM_000075.4:c.*301_*303dupTTT (chr12-57748221-T-TAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_000075.4(CDK4):c.*301_*303dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDK4
NM_000075.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.557

Publications

0 publications found

Variant links:

Genes affected

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

CDK4 links:

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

TSPAN31 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4 link	c.301_303dupTTT		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1	P11802-1A0A024RBB6
TSPAN31	NM_005981.5 link	c.943_945dupAAA		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1	Q12999

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11 link	c.301_303dupTTT		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5		P11802-1
TSPAN31	ENST00000257910.8 link	c.943_945dupAAA		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3		Q12999

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

137162

Hom.:

Cov.:

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:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

188878

Hom.:

Cov.:

AF XY:

0.0000618

AC XY:

AN XY:

97098

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

6690

American (AMR)

AF:

0.000152

AC:

AN:

6592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7182

East Asian (EAS)

AF:

0.00

AC:

AN:

15454

South Asian (SAS)

AF:

0.0000448

AC:

AN:

22322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

830

European-Non Finnish (NFE)

AF:

0.0000532

AC:

AN:

112768

Other (OTH)

AF:

0.00

AC:

AN:

11582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.244

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

137162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

66200

African (AFR)

AF:

0.00

AC:

AN:

37826

American (AMR)

AF:

0.00

AC:

AN:

13706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3218

East Asian (EAS)

AF:

0.00

AC:

AN:

4828

South Asian (SAS)

AF:

0.00

AC:

AN:

4346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62558

Other (OTH)

AF:

0.00

AC:

AN:

1838

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.56

Splicing

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

Publications

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NM_000075.4:c.301_303dupTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over