4-121828281-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176824.3(BBS7):c.1891-12C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,609,298 control chromosomes in the GnomAD database, including 447,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47679 hom., cov: 33)
  • Exomes 𝑓: 0.74 (399750 hom.)
• Consequence: BBS7 NM_176824.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005898
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.27

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-121828281-G-T is Benign according to our data. Variant chr4-121828281-G-T is described in ClinVar as [Benign]. Clinvar id is 262922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-121828281-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS7	NM_176824.3	c.1891-12C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264499.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS7	ENST00000264499.9	c.1891-12C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_176824.3	P1
BBS7	ENST00000506636.1	c.1891-12C>A		splice_polypyrimidine_tract_variant, intron_variant		1
BBS7	ENST00000507814.5	c.160-12C>A		splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119810 AN: 151994 Hom.: 47624 Cov.: 33

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.769 AC: 192361 AN: 250006 Hom.: 74751 AF XY: 0.759 AC XY: 102766 AN XY: 135308

Gnomad AFR exome AF: 0.893

Gnomad AMR exome AF: 0.869

Gnomad ASJ exome AF: 0.718

Gnomad EAS exome AF: 0.859

Gnomad SAS exome AF: 0.720

Gnomad FIN exome AF: 0.792

Gnomad NFE exome AF: 0.722

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.739 AC: 1077018 AN: 1457184 Hom.: 399750 Cov.: 36 AF XY: 0.737 AC XY: 534543 AN XY: 725148

Gnomad4 AFR exome AF: 0.894

Gnomad4 AMR exome AF: 0.861

Gnomad4 ASJ exome AF: 0.716

Gnomad4 EAS exome AF: 0.860

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.797

Gnomad4 NFE exome AF: 0.724

Gnomad4 OTH exome AF: 0.743

GnomAD4 genome AF: 0.788 AC: 119926 AN: 152114 Hom.: 47679 Cov.: 33 AF XY: 0.792 AC XY: 58890 AN XY: 74348

Gnomad4 AFR AF: 0.892

Gnomad4 AMR AF: 0.812

Gnomad4 ASJ AF: 0.722

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.794

Gnomad4 NFE AF: 0.724

Gnomad4 OTH AF: 0.750

Alfa AF: 0.750 Hom.: 12150

Bravo AF: 0.792

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bardet-Biedl syndrome 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.055
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00059
dbscSNV1_RF	Benign	0.020
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

Other links and lift over

dbSNP: rs2706793; hg19: chr4-122749436;