rs143149764
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Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_015681.6(B9D1):c.341+2T>C variant causes a splice donor change. The variant allele was found at a frequency of 0.000044 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )
Consequence
B9D1
NM_015681.6 splice_donor
NM_015681.6 splice_donor
Scores
3
3
1
Splicing: ADA: 0.9897
1
1
Clinical Significance
Conservation
PhyloP100: 6.48
Genes affected
B9D1 (HGNC:24123): (B9 domain containing 1) This gene encodes a B9 domain-containing protein, one of several that are involved in ciliogenesis. Alterations in expression of this gene have been found in a family with Meckel syndrome. Meckel syndrome has been associated with at least six different genes. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
?
Variant 17-19347782-A-G is Pathogenic according to our data. Variant chr17-19347782-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19347782-A-G is described in Lovd as [Pathogenic]. Variant chr17-19347782-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
B9D1 | NM_015681.6 | c.341+2T>C | splice_donor_variant | ENST00000261499.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
B9D1 | ENST00000261499.11 | c.341+2T>C | splice_donor_variant | 1 | NM_015681.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250828Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135660
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GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461526Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727064
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GnomAD4 genome ? AF: 0.0000919 AC: 14AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74486
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Meckel syndrome, type 9 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 06, 2015 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | This sequence change affects a donor splice site in intron 4 of the B9D1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs143149764, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with Meckel Gruber syndrome (PMID: 21493627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.505+2T>C. ClinVar contains an entry for this variant (Variation ID: 31102). Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a premature termination codon (PMID: 21493627). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Joubert syndrome 27 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Dec 13, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at