Variant summary: DTNBP1 c.162G>A (p.Arg54Arg) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 250182 control chromosomes. The observed variant frequency is approximately 4.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNBP1 causing Hermansky-Pudlak Syndrome phenotype (0.00016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.162G>A in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Conflicting interpretations of pathogenicity
Uncertain significance(2); Likely benign(1)
- Review status:
- criteria provided, conflicting interpretations
- Submissions:
- 3
- First in ClinVar:
- Oct 5, 2015
- Most recent Submission:
- Mar 28, 2022
- Last evaluated:
- Feb 15, 2022
- Accession:
- VCV000210857.8
- Variation ID:
- 210857
- Description:
- single nucleotide variant
Help
NM_032122.5(DTNBP1):c.162G>A (p.Arg54=)
- Allele ID
- 207338
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 6p22.3
- Genomic location
- 6: 15637804 (GRCh38) GRCh38 UCSC
- 6: 15638035 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_032122.5:c.162G>A MANE Select NP_115498.2:p.Arg54= synonymous NM_001271667.2:c.-82G>A 5 prime UTR NM_001271668.2:c.111G>A NP_001258597.1:p.Arg37= synonymous NM_001271669.2:c.57G>A NP_001258598.1:p.Gly19= synonymous NM_183040.2:c.162G>A NP_898861.1:p.Arg54= synonymous NR_036448.3:n.460G>A NC_000006.12:g.15637804C>T NC_000006.11:g.15638035C>T NG_009309.1:g.30237G>A LRG_588:g.30237G>A LRG_588t1:c.162G>A LRG_588p1:p.Arg54= LRG_588t2:c.162G>A LRG_588p2:p.Arg54= - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000006.12:15637803:C:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- 0.00120 (G)
- Allele frequency
- 1000 Genomes Project 0.00060
- NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
- The Genome Aggregation Database (gnomAD) 0.00077
- Trans-Omics for Precision Medicine (TOPMed) 0.00063
- Links
- ClinGen: CA209841
- dbSNP: rs77460377
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Uncertain significance | 1 | criteria provided, single submitter | Dec 8, 2021 | RCV001852553.2 | |
| Conflicting interpretations of pathogenicity | 2 | criteria provided, conflicting interpretations | Feb 15, 2022 | RCV000195186.7 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Uncertain significance
(Jun 25, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory,University of Chicago
Accession: SCV000247197.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Likely benign
(Feb 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002104021.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: DTNBP1 c.162G>A (p.Arg54Arg) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more)
Variant summary: DTNBP1 c.162G>A (p.Arg54Arg) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 250182 control chromosomes. The observed variant frequency is approximately 4.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNBP1 causing Hermansky-Pudlak Syndrome phenotype (0.00016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.162G>A in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Uncertain significance
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002278108.1
First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
Comment:
This sequence change affects codon 54 of the DTNBP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 54 of the DTNBP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DTNBP1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs77460377, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DTNBP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 210857). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. (less)
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| There are no citations in ClinVar for this variation. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs77460377...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jun 24, 2022