NM_005981.5:c.*2031T>A
Variant names:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_005981.5(TSPAN31):c.*2031T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
TSPAN31
NM_005981.5 3_prime_UTR
NM_005981.5 3_prime_UTR
Scores
2
Splicing: ADA: 0.002287
2
Clinical Significance
Conservation
PhyloP100: -0.169
Genes affected
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]
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 12-57749321-T-A is Benign according to our data. Variant chr12-57749321-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 142091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TSPAN31 | NM_005981.5 | c.*2031T>A | 3_prime_UTR_variant | Exon 6 of 6 | ENST00000257910.8 | NP_005972.1 | ||
| CDK4 | NM_000075.4 | c.684-4A>T | splice_region_variant, intron_variant | Intron 6 of 7 | ENST00000257904.11 | NP_000066.1 | ||
| TSPAN31 | NM_001330169.2 | c.*2031T>A | 3_prime_UTR_variant | Exon 6 of 6 | NP_001317098.1 | |||
| TSPAN31 | NM_001330168.2 | c.*2031T>A | 3_prime_UTR_variant | Exon 4 of 4 | NP_001317097.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TSPAN31 | ENST00000257910.8 | c.*2031T>A | 3_prime_UTR_variant | Exon 6 of 6 | 1 | NM_005981.5 | ENSP00000257910.3 | |||
| CDK4 | ENST00000257904.11 | c.684-4A>T | splice_region_variant, intron_variant | Intron 6 of 7 | 1 | NM_000075.4 | ENSP00000257904.5 |
Frequencies
GnomAD3 genomes 0.000145 AC: 22AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251296Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135834
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GnomAD4 exome AF: 0.000150 AC: 219AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125AN XY: 727228
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GnomAD4 genome 0.000145 AC: 22AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74330
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 22, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | This variant is associated with the following publications: (PMID: 25980754) - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 21, 2016 | Variant summary: The CDK4 c.684-4A>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicting alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 21/121132 (1/5767), predominantly in the European (Non-Finnish) cohort, 19/66612 (1/3506), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CDK4 variant of 1/50000. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. The variant of interest has been reported in affected individuals via publications, however, cosegregation data was not provided. Clinical diagnostic laboratories have cited the variant with conflicting classifications "uncertain siginficance" or "likely benign," without any additional information to provide an independent evaluation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. - |
Melanoma, cutaneous malignant, susceptibility to, 3 Benign:2
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 26, 2024 | This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Hereditary cancer-predisposing syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Familial melanoma Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at