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rs119466002

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_176824.3(BBS7):c.632C>T(p.Thr211Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 779,484 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T211R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

BBS7
NM_176824.3 missense

Scores

8
10
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.46
Variant links:
Genes affected
BBS7 (HGNC:18758): (Bardet-Biedl syndrome 7) This gene encodes one of eight proteins that form the BBSome complex containing BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. The BBSome complex is believed to recruit Rab8(GTP) to the primary cilium and promote ciliogenesis. The BBSome complex assembly is mediated by a complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins. Mutations in this gene are implicated in Bardet-Biedl syndrome, a genetic disorder whose symptoms include obesity, retinal degeneration, polydactyly and nephropathy; however, mutations in this gene and the BBS8 gene are thought to play a minor role and mutations in chaperonin-like BBS genes are found to be a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. Two transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Oct 2014]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911
PP5
Variant 4-121854790-G-A is Pathogenic according to our data. Variant chr4-121854790-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BBS7NM_176824.3 linkuse as main transcriptc.632C>T p.Thr211Ile missense_variant 7/19 ENST00000264499.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BBS7ENST00000264499.9 linkuse as main transcriptc.632C>T p.Thr211Ile missense_variant 7/191 NM_176824.3 P1Q8IWZ6-1
BBS7ENST00000506636.1 linkuse as main transcriptc.632C>T p.Thr211Ile missense_variant 7/181 Q8IWZ6-2

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152006
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000525
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:
0.000481
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251334
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000175
AC:
11
AN:
627478
Hom.:
0
Cov.:
30
AF XY:
0.0000175
AC XY:
6
AN XY:
341888
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000183
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:
0.00000286
Gnomad4 OTH exome
AF:
0.0000606
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152006
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74262
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000525
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:
0.000481
Bravo
AF:
0.000174
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 7 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 19, 2023- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 27, 2022- -
Bardet-Biedl syndrome 1/7, digenic Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2003- -
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 03, 2024This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 211 of the BBS7 protein (p.Thr211Ile). This variant is present in population databases (rs119466002, gnomAD 0.0009%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 12567324, 21642631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS7 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS7 function (PMID: 20498079, 22500027, 23572516). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
Cadd
Pathogenic
29
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.74
D;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Uncertain
2.9
M;M
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-4.4
D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.040
D;D
Polyphen
1.0
D;.
Vest4
0.98
MutPred
0.72
Loss of disorder (P = 0.053);Loss of disorder (P = 0.053);
MVP
0.98
MPC
0.72
ClinPred
0.98
D
GERP RS
5.7
Varity_R
0.43
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs119466002; hg19: chr4-122775945; API