chr6-83854160-A-T
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001400774.1(RIPPLY2-CYB5R4):c.-29A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000172 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
RIPPLY2-CYB5R4
NM_001400774.1 5_prime_UTR_premature_start_codon_gain
NM_001400774.1 5_prime_UTR_premature_start_codon_gain
Scores
2
3
2
Splicing: ADA: 0.3610
2
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
RIPPLY2 (HGNC:21390): (ripply transcriptional repressor 2) This gene encodes a nuclear protein that belongs to a novel family of proteins required for vertebrate somitogenesis. Members of this family have a tetrapeptide WRPW motif that is required for interaction with the transcriptional repressor Groucho and a carboxy-terminal Ripply homology domain/Bowline-DSCR-Ledgerline conserved region required for transcriptional repression. Null mutant mice die soon after birth and display defects in axial skeleton segmentation due to defective somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.421
PP5
Variant 6-83854160-A-T is Pathogenic according to our data. Variant chr6-83854160-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221271.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Pathogenic=2}. Variant chr6-83854160-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RIPPLY2 | NM_001009994.3 | c.238A>T | p.Arg80* | stop_gained, splice_region_variant | 3/4 | ENST00000369689.6 | NP_001009994.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RIPPLY2 | ENST00000369689.6 | c.238A>T | p.Arg80* | stop_gained, splice_region_variant | 3/4 | 1 | NM_001009994.3 | ENSP00000358703.1 | ||
RIPPLY2 | ENST00000369687.2 | c.64A>T | p.Arg22* | stop_gained, splice_region_variant | 2/3 | 2 | ENSP00000358701.1 | |||
RIPPLY2 | ENST00000635617.1 | n.571A>T | non_coding_transcript_exon_variant | 1/1 | 6 | |||||
ENSG00000287705 | ENST00000656981.1 | n.8T>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000123 AC: 31AN: 251422Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135908
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GnomAD4 exome AF: 0.000167 AC: 244AN: 1461472Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 119AN XY: 727048
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GnomAD4 genome AF: 0.000223 AC: 34AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74376
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | RIPPLY2: PVS1:Strong, PM2, PM3, PP4, PS3:Supporting - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 08, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg80*) in the RIPPLY2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the RIPPLY2 protein. This variant is present in population databases (rs201419367, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with multiple segmentation defects (PMID: 25343988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 221271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Spondylocostal dysostosis 6, autosomal recessive Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 05, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2015 | - - |
Spondylocostal dysostosis 2, autosomal recessive Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
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Calibrated prediction
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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