rs61764067

chr7-33340944-G-Achr7-33340944-G-T

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.1246G>A(p.Val416Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,613,512 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (34 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.25

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=0.0039181113).
• BP6: Variant 7-33340944-G-A is Benign according to our data. Variant chr7-33340944-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33340944-G-A is described in Lovd as [Likely_benign]. Variant chr7-33340944-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00389 (592/152152) while in subpopulation EAS AF= 0.0155 (80/5174). AF 95% confidence interval is 0.0127. There are 4 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.1246G>A	p.Val416Met	missense_variant	11/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.1246G>A	p.Val416Met	missense_variant	11/23	1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152034 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00957

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00746

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00607 AC: 1526 AN: 251382 Hom.: 6 AF XY: 0.00551 AC XY: 748 AN XY: 135864

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0132

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00401 AC: 5866 AN: 1461360 Hom.: 34 Cov.: 30 AF XY: 0.00395 AC XY: 2869 AN XY: 726968

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.00961

Gnomad4 EAS exome AF: 0.0244

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00669

Gnomad4 NFE exome AF: 0.00276

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152152 Hom.: 4 Cov.: 32 AF XY: 0.00397 AC XY: 295 AN XY: 74398

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00955

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00746

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00380 Hom.: 3

Bravo AF: 0.00413

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00556 AC: 675

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2014	- -

Bardet-Biedl syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 12, 2017	- -

Bardet-Biedl syndrome 9 Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.011
Dann	Benign	0.77
DEOGEN2	Benign	0.056	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.78	T;T;T;T
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0070	B;B;B;.
Vest4		0.11
MVP		0.43
MPC		0.064
ClinPred		0.0070	T
GERP RS		-9.0
Varity_R		0.058
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs61764067; hg19: chr7-33380556; COSMIC: COSV54169251; COSMIC: COSV54169251;