chr15-72686229-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_033028.5(BBS4):ā€‹c.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

Scores

4
4
8

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.70
Variant links:
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]

Genome browser will be placed here

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
BBS4NM_033028.5 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/16 ENST00000268057.9
HIGD2BNM_001350932.3 linkuse as main transcript upstream_gene_variant ENST00000311755.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BBS4ENST00000268057.9 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/161 NM_033028.5 P1Q96RK4-1
HIGD2BENST00000311755.6 linkuse as main transcript upstream_gene_variant 1 NM_001350932.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000565
AC:
1
AN:
177122
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
94232
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000370
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000566
AC:
8
AN:
1412618
Hom.:
0
Cov.:
31
AF XY:
0.00000573
AC XY:
4
AN XY:
698122
show subpopulations
Gnomad4 AFR exome
AF:
0.0000309
Gnomad4 AMR exome
AF:
0.0000264
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000368
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
Cov.:
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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 31, 2017- -
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeAug 17, 2023For 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Benign
0.23
T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.15
FATHMM_MKL
Benign
0.60
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.67
T
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-0.84
N
REVEL
Uncertain
0.35
Sift
Uncertain
0.011
D
Sift4G
Uncertain
0.013
D
Polyphen
0.067
B
Vest4
0.78
MutPred
0.99
Gain of helix (P = 0.0199);
MVP
0.81
ClinPred
0.98
D
GERP RS
3.7
Varity_R
0.79
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1302879683; hg19: chr15-72978570; API