rs142434516

chr7-33533991-T-Achr7-33533991-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP3 BP4_Strong BP6 BS1

The NM_198428.3(BBS9):c.2336T>A(p.Leu779Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,614,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L779L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.45

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, PROVEAN, REVEL [when BayesDel_addAF, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.04413256).
• BP6: Variant 7-33533991-T-A is Benign according to our data. Variant chr7-33533991-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242248.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00171 (260/152356) while in subpopulation AFR AF= 0.00594 (247/41578). AF 95% confidence interval is 0.00533. There are 1 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.2336T>A	p.Leu779Gln	missense_variant	21/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.2336T>A	p.Leu779Gln	missense_variant	21/23	1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000477 AC: 120 AN: 251484 Hom.: 1 AF XY: 0.000375 AC XY: 51 AN XY: 135918

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.000202

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1461894 Hom.: 0 Cov.: 30 AF XY: 0.000143 AC XY: 104 AN XY: 727248

Gnomad4 AFR exome AF: 0.00657

Gnomad4 AMR exome AF: 0.000112

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: 0.00000540

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74510

Gnomad4 AFR AF: 0.00594

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.00205

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	Reported in the heterozygous state in an individual with Bardet-Biedl syndrome (BBS) who was not found to have a second BBS9 variant but did harbor a variant in another BBS-related gene; however, familial segregation information was not provided for either variant (Janssen et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21052717) -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 19, 2022

DNA sequence analysis of the BBS9 gene demonstrated a sequence change, c.2336T>A, in exon 21 that results in an amino acid change, p.Leu779Gln. This sequence change has been described in the gnomAD database with a frequency of 0.66% in the African/African American subpopulation and includes one individual homozygous for this variant (dbSNP rs142434516). The p.Leu779Gln change affects a highly conserved amino acid residue located in a domain of the BBS9 protein that is not known to be functional. The p.Leu779Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in an individual with Bardet-Biedl syndrome in the heterozygous state, however a second variant in BBS9 or another BBS-related gene was not identified (PMID: 21052717). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu779Gln change remains unknown at this time. -

Bardet-Biedl syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.94
MVP		0.77
MPC		0.40
ClinPred		0.069	T
GERP RS		5.8
Varity_R		0.89
gMVP		0.73

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: rs142434516; hg19: chr7-33573603;