chr15-72686229-T-C
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_033028.5(BBS4):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,412,618 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 (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000057 ( 0 hom. )
Consequence
BBS4
NM_033028.5 start_lost
NM_033028.5 start_lost
Scores
4
4
8
Clinical Significance
Conservation
PhyloP100: 2.70
Genes affected
BBS4 (HGNC:969): (Bardet-Biedl syndrome 4) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
HIGD2B (HGNC:26984): (HIG1 hypoxia inducible domain family member 2B) Predicted to be involved in mitochondrial respirasome assembly. Predicted to be integral component of membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_033028.5 (BBS4) was described as [Likely_pathogenic] in ClinVar as 886465
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-72686229-T-C is Pathogenic according to our data. Variant chr15-72686229-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 445809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS4 | NM_033028.5 | c.2T>C | p.Met1? | start_lost | 1/16 | ENST00000268057.9 | |
HIGD2B | NM_001350932.3 | upstream_gene_variant | ENST00000311755.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS4 | ENST00000268057.9 | c.2T>C | p.Met1? | start_lost | 1/16 | 1 | NM_033028.5 | P1 | |
HIGD2B | ENST00000311755.6 | upstream_gene_variant | 1 | NM_001350932.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000565 AC: 1AN: 177122Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 94232
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GnomAD4 exome AF: 0.00000566 AC: 8AN: 1412618Hom.: 0 Cov.: 31 AF XY: 0.00000573 AC XY: 4AN XY: 698122
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GnomAD4 genome Cov.: 32
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 31, 2017 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 17, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BBS4 protein in which other variant(s) (Deletion (Exons 3-4)) have been determined to be pathogenic (PMID: 11381270). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 445809). This variant has not been reported in the literature in individuals affected with BBS4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the BBS4 mRNA. The next in-frame methionine is located at codon 173. - |
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
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of helix (P = 0.0199);
MVP
ClinPred
D
GERP RS
Varity_R
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