chr4-121854706-CCTCT-C

Position:

chr4-121854706-CCTCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_176824.3(BBS7):c.712_715del(p.Arg238GlufsTer59) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,611,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

BBS7
NM_176824.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 7.25

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]

BBS7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-121854706-CCTCT-C is Pathogenic according to our data. Variant chr4-121854706-CCTCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 281626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-121854706-CCTCT-C is described in Lovd as [Pathogenic]. Variant chr4-121854706-CCTCT-C is described in Lovd as [Pathogenic]. Variant chr4-121854706-CCTCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS7	NM_176824.3 linkuse as main transcript	c.712_715del	p.Arg238GlufsTer59	frameshift_variant	7/19	ENST00000264499.9	NP_789794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS7	ENST00000264499.9 linkuse as main transcript	c.712_715del	p.Arg238GlufsTer59	frameshift_variant	7/19	1	NM_176824.3	ENSP00000264499	P1	Q8IWZ6-1
BBS7	ENST00000506636.1 linkuse as main transcript	c.712_715del	p.Arg238GlufsTer59	frameshift_variant	7/18	1		ENSP00000423626		Q8IWZ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250940

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135630

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:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000418

AC:

AN:

1459156

Hom.:

AF XY:

0.0000413

AC XY:

AN XY:

725916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000522

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -

Bardet-Biedl syndrome 7

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.712_715del (p.Arg238GlufsTer59) frameshift variant in BBS7 gene has been has been observed to be homozygous or in combination with another BBS7 variant in individuals with Bardet-Biedl Syndrome (Ece et al., 2015; Bin et al., 2009). The p.Pro790GlnfsTer98 variant is reported with the allele frequency (0.005%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Arginine 238, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 59 of the new reading frame, denoted p.Arg238GlufsTer59. Loss-of-function variants in BBS7 are known to be pathogenic (Badano et al., 2003). For these reasons, this variant has been classified as Pathogenic. -

BBS7-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2024

The BBS7 c.712_715delAGAG variant is predicted to result in a frameshift and premature protein termination (p.Arg238Glufs*59). This variant has been reported in the homozygous or compound heterozygous state in individuals with Bardet-Biedl syndrome (Bin et al. 2009. PubMed ID: 19402160; Ece Solmaz et al. 2015. PubMed ID: 26518167), and chain terminating variants in BBS7 are a well-established mechanism of pathogenicity. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Bardet-Biedl syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Advanced Center For Translational And Genetic Medicine, Ann & Robert H. Lurie Children's Hospital Of Chicago

May 10, 2023

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 07, 2018

- -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change creates a premature translational stop signal (p.Arg238Glufs*59) in the BBS7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS7 are known to be pathogenic (PMID: 12567324, 19402160, 21209035, 31196119). This variant is present in population databases (rs760165634, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Bardet-Biedl Syndrome (PMID: 19402160, 26518167). ClinVar contains an entry for this variant (Variation ID: 281626). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over