chr2-169479554-A-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong
The NM_152384.3(BBS5):c.1A>T(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000186 in 1,614,128 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
BBS5
NM_152384.3 initiator_codon
NM_152384.3 initiator_codon
Scores
4
3
9
Clinical Significance
Conservation
PhyloP100: 5.89
Genes affected
BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 63 CDS bases. Genomic position: 169482254. Lost 0.061 part of the original CDS.
PS1
Another start lost variant in NM_152384.3 (BBS5) was described as [Likely_pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-169479554-A-T is Pathogenic according to our data. Variant chr2-169479554-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3014382.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 |
---|---|---|---|---|---|---|---|---|
BBS5 | NM_152384.3 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 12 | ENST00000295240.8 | NP_689597.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BBS5 | ENST00000295240.8 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 12 | 1 | NM_152384.3 | ENSP00000295240.3 | ||
ENSG00000251569 | ENST00000513963.1 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 16 | 2 | ENSP00000424363.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249786Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135166
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461828Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727220
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152300Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74472
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 17, 2024 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 18, 2023 | For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 19797195, 25982971). This variant is present in population databases (rs536117380, gnomAD 0.007%). This sequence change affects the initiator methionine of the BBS5 mRNA. The next in-frame methionine is located at codon 22. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MutPred
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at