4-121848812-T-C

Variant names:

• chr4-121848812-T-C
• rs6824258
• NM_176824.3:c.934+32A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176824.3(BBS7):​c.934+32A>G variant causes a intron change. The variant allele was found at a frequency of 0.252 in 1,476,652 control chromosomes in the GnomAD database, including 46,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (3867 hom., cov: 30)
  • Exomes 𝑓: 0.25 (42679 hom.)
• Consequence: BBS7 NM_176824.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.88
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-121848812-T-C is Benign according to our data. Variant chr4-121848812-T-C is described in ClinVar as Benign. ClinVar VariationId is 262924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS7	NM_176824.3	c.934+32A>G		intron_variant	Intron 9 of 18	ENST00000264499.9	NP_789794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS7	ENST00000264499.9	c.934+32A>G		intron_variant	Intron 9 of 18	1	NM_176824.3	ENSP00000264499.4
BBS7	ENST00000506636.1	c.934+32A>G		intron_variant	Intron 9 of 17	1		ENSP00000423626.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 31826 AN: 124484 Hom.: 3866 Cov.: 30

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.231 AC: 57577 AN: 249166 AF XY: 0.230

Gnomad AFR exome AF: 0.0940

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.252 AC: 340466 AN: 1352126 Hom.: 42679 Cov.: 22 AF XY: 0.250 AC XY: 169342 AN XY: 677476

African (AFR) AF: 0.222 AC: 3031 AN: 13654

American (AMR) AF: 0.260 AC: 10966 AN: 42194

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 6741 AN: 23774

East Asian (EAS) AF: 0.139 AC: 5265 AN: 37804

South Asian (SAS) AF: 0.167 AC: 14001 AN: 83680

European-Finnish (FIN) AF: 0.310 AC: 16091 AN: 51846

Middle Eastern (MID) AF: 0.194 AC: 1000 AN: 5162

European-Non Finnish (NFE) AF: 0.260 AC: 270253 AN: 1039440

Other (OTH) AF: 0.240 AC: 13118 AN: 54572

GnomAD4 genome AF: 0.256 AC: 31823 AN: 124526 Hom.: 3867 Cov.: 30 AF XY: 0.256 AC XY: 15720 AN XY: 61368

African (AFR) AF: 0.224 AC: 4141 AN: 18488

American (AMR) AF: 0.266 AC: 3671 AN: 13784

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 889 AN: 3202

East Asian (EAS) AF: 0.158 AC: 781 AN: 4928

South Asian (SAS) AF: 0.148 AC: 706 AN: 4760

European-Finnish (FIN) AF: 0.323 AC: 3393 AN: 10498

Middle Eastern (MID) AF: 0.197 AC: 50 AN: 254

European-Non Finnish (NFE) AF: 0.266 AC: 17536 AN: 65912

Other (OTH) AF: 0.257 AC: 460 AN: 1792

Alfa AF: 0.235 Hom.: 665

Bravo AF: 0.198

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		3.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6824258; hg19: chr4-122769967; COSMIC: COSV52656158;