rs34209904

chr7-33383725-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198428.3(BBS9):c.1849A>C(p.Ile617Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,612,222 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (40 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.75

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043776035).
• BP6: Variant 7-33383725-A-C is Benign according to our data. Variant chr7-33383725-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 263122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33383725-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1781/152318) while in subpopulation AFR AF= 0.0405 (1681/41556). AF 95% confidence interval is 0.0388. There are 37 homozygotes in gnomad4. There are 838 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.1849A>C	p.Ile617Leu	missense_variant	18/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.1849A>C	p.Ile617Leu	missense_variant	18/23	1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1777 AN: 152200 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00318 AC: 790 AN: 248454 Hom.: 12 AF XY: 0.00247 AC XY: 332 AN XY: 134208

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.00262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000892

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00129 AC: 1880 AN: 1459904 Hom.: 40 Cov.: 31 AF XY: 0.00115 AC XY: 835 AN XY: 726110

Gnomad4 AFR exome AF: 0.0449

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00289

GnomAD4 genome AF: 0.0117 AC: 1781 AN: 152318 Hom.: 37 Cov.: 32 AF XY: 0.0112 AC XY: 838 AN XY: 74500

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00272 Hom.: 16

Bravo AF: 0.0143

ESP6500AA AF: 0.0425 AC: 187

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00404 AC: 490

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bardet-Biedl syndrome 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 04, 2017

- -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	0.92	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0040	B;B;B;.
Vest4		0.53
MVP		0.32
MPC		0.065
ClinPred		0.0055	T
GERP RS		6.1
Varity_R		0.21
gMVP		0.27

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: rs34209904; hg19: chr7-33423337;