rs876659522
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000075.4(CDK4):c.841C>T(p.His281Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H281D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.841C>T | p.His281Tyr | missense_variant | 8/8 | ENST00000257904.11 | |
TSPAN31 | NM_005981.5 | c.*1306G>A | 3_prime_UTR_variant | 6/6 | ENST00000257910.8 | ||
MIR6759 | NR_106817.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.841C>T | p.His281Tyr | missense_variant | 8/8 | 1 | NM_000075.4 | P1 | |
TSPAN31 | ENST00000257910.8 | c.*1306G>A | 3_prime_UTR_variant | 6/6 | 1 | NM_005981.5 | P1 | ||
MIR6759 | ENST00000638110.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251442Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461430Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727058
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 17, 2024 | The p.H281Y variant (also known as c.841C>T), located in coding exon 7 of the CDK4 gene, results from a C to T substitution at nucleotide position 841. The histidine at codon 281 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 281 of the CDK4 protein (p.His281Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 483309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDK4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Melanoma, cutaneous malignant, susceptibility to, 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at