rs190881240
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001111.5(ADAR):c.2668+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,954 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0024 ( 18 hom. )
Consequence
ADAR
NM_001111.5 splice_donor_region, intron
NM_001111.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.006582
2
Clinical Significance
Conservation
PhyloP100: -0.196
Genes affected
ADAR (HGNC:225): (adenosine deaminase RNA specific) This gene encodes the enzyme responsible for RNA editing by site-specific deamination of adenosines. This enzyme destabilizes double-stranded RNA through conversion of adenosine to inosine. Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
?
Variant 1-154589751-A-G is Benign according to our data. Variant chr1-154589751-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 292766.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr1-154589751-A-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00235 (3437/1461864) while in subpopulation SAS AF= 0.00573 (494/86254). AF 95% confidence interval is 0.00531. There are 18 homozygotes in gnomad4_exome. There are 1774 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome at 7 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAR | NM_001111.5 | c.2668+6T>C | splice_donor_region_variant, intron_variant | ENST00000368474.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAR | ENST00000368474.9 | c.2668+6T>C | splice_donor_region_variant, intron_variant | 1 | NM_001111.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00139 AC: 211AN: 151972Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00207 AC: 520AN: 251294Hom.: 7 AF XY: 0.00233 AC XY: 317AN XY: 135814
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GnomAD4 exome AF: 0.00235 AC: 3437AN: 1461864Hom.: 18 Cov.: 32 AF XY: 0.00244 AC XY: 1774AN XY: 727232
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GnomAD4 genome ? AF: 0.00138 AC: 210AN: 152090Hom.: 0 Cov.: 31 AF XY: 0.00121 AC XY: 90AN XY: 74358
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | ADAR: BP4, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2020 | - - |
Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | ADAR NM_001111.4 exon 8 c.2668+6T>C: This variant has not been reported in the literature but is present in 0.5% (161/30782) of South Asian alleles, including 5 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs190881240). This variant is present in ClinVar (Variation ID:292766). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Symmetrical dyschromatosis of extremities Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
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
Prediction
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