chr4-121843997-T-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PP2PP3BP4_StrongBS1BS2

The NM_176824.3(BBS7):​c.1235A>G​(p.Asp412Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,584,246 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D412Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

BBS7
NM_176824.3 missense

Scores

8
9
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 6.19
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2326 (below the threshold of 3.09). Trascript score misZ: 1.7868 (below the threshold of 3.09). GenCC associations: The gene is linked to ciliopathy, Bardet-Biedl syndrome, Bardet-Biedl syndrome 7.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.04046455).
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (223/152178) while in subpopulation NFE AF = 0.0024 (163/68002). AF 95% confidence interval is 0.0021. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BBS7NM_176824.3 linkc.1235A>G p.Asp412Gly missense_variant Exon 12 of 19 ENST00000264499.9 NP_789794.1 Q8IWZ6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BBS7ENST00000264499.9 linkc.1235A>G p.Asp412Gly missense_variant Exon 12 of 19 1 NM_176824.3 ENSP00000264499.4 Q8IWZ6-1
BBS7ENST00000506636.1 linkc.1235A>G p.Asp412Gly missense_variant Exon 12 of 18 1 ENSP00000423626.1 Q8IWZ6-2

Frequencies

GnomAD3 genomes
AF:
0.00147
AC:
223
AN:
152060
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000387
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00240
Gnomad OTH
AF:
0.00192
GnomAD2 exomes
AF:
0.00149
AC:
334
AN:
224248
AF XY:
0.00146
show subpopulations
Gnomad AFR exome
AF:
0.000567
Gnomad AMR exome
AF:
0.00104
Gnomad ASJ exome
AF:
0.00441
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000971
Gnomad NFE exome
AF:
0.00241
Gnomad OTH exome
AF:
0.000887
GnomAD4 exome
AF:
0.00207
AC:
2967
AN:
1432068
Hom.:
4
Cov.:
26
AF XY:
0.00202
AC XY:
1439
AN XY:
711796
show subpopulations
Gnomad4 AFR exome
AF:
0.000424
AC:
14
AN:
33022
Gnomad4 AMR exome
AF:
0.00116
AC:
50
AN:
43190
Gnomad4 ASJ exome
AF:
0.00501
AC:
128
AN:
25524
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39332
Gnomad4 SAS exome
AF:
0.000394
AC:
33
AN:
83766
Gnomad4 FIN exome
AF:
0.000229
AC:
12
AN:
52388
Gnomad4 NFE exome
AF:
0.00241
AC:
2622
AN:
1090024
Gnomad4 Remaining exome
AF:
0.00179
AC:
106
AN:
59142
Heterozygous variant carriers
0
118
236
354
472
590
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
98
196
294
392
490
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00147
AC:
223
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.00128
AC XY:
95
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.000385
AC:
0.000385375
AN:
0.000385375
Gnomad4 AMR
AF:
0.00170
AC:
0.00169957
AN:
0.00169957
Gnomad4 ASJ
AF:
0.00288
AC:
0.00288351
AN:
0.00288351
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000415
AC:
0.000415282
AN:
0.000415282
Gnomad4 FIN
AF:
0.000189
AC:
0.000188893
AN:
0.000188893
Gnomad4 NFE
AF:
0.00240
AC:
0.00239699
AN:
0.00239699
Gnomad4 OTH
AF:
0.00190
AC:
0.00189753
AN:
0.00189753
Heterozygous variant carriers
0
11
21
32
42
53
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00222
Hom.:
4
Bravo
AF:
0.00164
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000911
AC:
4
ESP6500EA
AF:
0.00209
AC:
18
ExAC
AF:
0.00129
AC:
156

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
May 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

BBS7: PP3 -

Oct 16, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in the heterozygous state in a patient with retinal dystrophy, postaxial polydactyly, and intellectual disability who also harbored a homozgyous variant in the BBS1 gene (Perea-Romero et al., 2022); This variant is associated with the following publications: (PMID: 25533962, 31376382, 35835773) -

Bardet-Biedl syndrome 7 Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy Uncertain:1
Jan 01, 2022
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

BBS7-related ciliopathy Benign:1
Aug 26, 2020
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Bardet-Biedl syndrome Benign:1
Jan 24, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Uncertain
0.048
T
BayesDel_noAF
Pathogenic
0.30
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.040
T;T
MetaSVM
Uncertain
0.22
D
MutationAssessor
Pathogenic
3.1
M;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.019
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
0.92
P;.
Vest4
0.75
MVP
0.95
MPC
0.47
ClinPred
0.032
T
GERP RS
6.1
Varity_R
0.64
gMVP
0.66
Mutation Taster
=88/12
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs111442398; hg19: chr4-122765152; COSMIC: COSV52659143; API