7-33130048-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198428.3(BBS9):c.-12+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,182 control chromosomes in the GnomAD database, including 2,033 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2033 hom., cov: 32)
  • Exomes 𝑓: 0.22 (0 hom.)
• Consequence: BBS9 NM_198428.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003683
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0120

Genes affected

BBS9 (HGNC:30000): (Bardet-Biedl syndrome 9) This gene is downregulated by parathyroid hormone in osteoblastic cells, and therefore is thought to be involved in parathyroid hormone action in bones. The exact function of this gene has not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-33130048-T-C is Benign according to our data. Variant chr7-33130048-T-C is described in ClinVar as [Benign]. Clinvar id is 360059.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-33130048-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.-12+7T>C		splice_region_variant, intron_variant		ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.-12+7T>C		splice_region_variant, intron_variant		1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23532 AN: 152032 Hom.: 2033 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.219 AC: 7 AN: 32 Hom.: 0 Cov.: 0 AF XY: 0.222 AC XY: 4 AN XY: 18

Gnomad4 AMR exome AF: 0.500

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.155 AC: 23560 AN: 152150 Hom.: 2033 Cov.: 32 AF XY: 0.156 AC XY: 11636 AN XY: 74362

Gnomad4 AFR AF: 0.0765

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.169

Alfa AF: 0.163 Hom.: 395

Bravo AF: 0.148

Asia WGS AF: 0.200 AC: 694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome 9 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.2
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.14		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: rs1468797; hg19: chr7-33169660;