chr2-169479554-A-T

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

Scores

4
3
9

Clinical Significance

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

Conservation

PhyloP100: 5.89
Variant links:
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]

Genome browser will be placed here

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
BBS5NM_152384.3 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 12 ENST00000295240.8 NP_689597.1 Q8N3I7-1A0A0S2Z626

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BBS5ENST00000295240.8 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 12 1 NM_152384.3 ENSP00000295240.3 Q8N3I7-1
ENSG00000251569ENST00000513963.1 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 16 2 ENSP00000424363.1 E9PBE3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152182
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249786
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135166
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
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:
6.84e-7
AC:
1
AN:
1461828
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152300
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

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 submitterresearchGenomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research CentreMar 17, 2024- -
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 18, 2023For 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.26
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Benign
0.14
T;.;.
Eigen
Benign
0.0085
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Benign
-0.68
T
PROVEAN
Benign
-0.87
N;N;N
REVEL
Uncertain
0.36
Sift
Benign
0.16
T;T;T
Sift4G
Benign
0.58
T;T;T
Polyphen
0.0010
B;B;.
Vest4
0.93
MutPred
0.96
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
0.80
ClinPred
0.92
D
GERP RS
6.0
Varity_R
0.32
gMVP
0.31

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: rs536117380; hg19: chr2-170336064; API