4-121825441-A-T

Position:

• chr4-121825441-A-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.*419T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 153,848 control chromosomes in the GnomAD database, including 8,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8340 hom., cov: 33)
  • Exomes 𝑓: 0.37 (133 hom.)
• Consequence: BBS7 NM_176824.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.68

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=-0.54).
• BP6: Variant 4-121825441-A-T is Benign according to our data. Variant chr4-121825441-A-T is described in ClinVar as [Benign]. Clinvar id is 347476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS7	NM_176824.3	c.*419T>A		3_prime_UTR_variant	19/19	ENST00000264499.9	NP_789794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS7	ENST00000264499	c.*419T>A		3_prime_UTR_variant	19/19	1	NM_176824.3	ENSP00000264499.4
BBS7	ENST00000507814.5	c.*13-213T>A		intron_variant		3		ENSP00000423250.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45578 AN: 152018 Hom.: 8332 Cov.: 33

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.324

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.372 AC: 637 AN: 1712 Hom.: 133 Cov.: 0 AF XY: 0.350 AC XY: 328 AN XY: 936

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.409

Gnomad4 EAS exome AF: 0.404

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.372

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.300 AC: 45593 AN: 152136 Hom.: 8340 Cov.: 33 AF XY: 0.304 AC XY: 22607 AN XY: 74358

Gnomad4 AFR AF: 0.0777

Gnomad4 AMR AF: 0.406

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.305

Alfa AF: 0.323 Hom.: 1094

Bravo AF: 0.290

Asia WGS AF: 0.363 AC: 1264 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 7 Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.6
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs3762840; hg19: chr4-122746596;