rs116262072

chr7-33388022-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198428.3(BBS9):c.1993C>T(p.Leu665Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000623 in 1,613,994 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.67

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065787733).
• BP6: Variant 7-33388022-C-T is Benign according to our data. Variant chr7-33388022-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166740.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=2}. Variant chr7-33388022-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00365 (555/152186) while in subpopulation AFR AF= 0.0126 (523/41512). AF 95% confidence interval is 0.0117. There are 4 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.1993C>T	p.Leu665Phe	missense_variant	19/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.1993C>T	p.Leu665Phe	missense_variant	19/23	1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152068 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000943 AC: 237 AN: 251434 Hom.: 0 AF XY: 0.000648 AC XY: 88 AN XY: 135890

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000925

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: 0.0000440

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461808 Hom.: 1 Cov.: 31 AF XY: 0.000230 AC XY: 167 AN XY: 727202

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.00365 AC: 555 AN: 152186 Hom.: 4 Cov.: 32 AF XY: 0.00358 AC XY: 266 AN XY: 74388

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000627 Hom.: 2

Bravo AF: 0.00407

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -

Bardet-Biedl syndrome 9 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 06, 2022	- -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	0.86	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.061	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.95	P;P;P;.
Vest4		0.89
MVP		0.29
MPC		0.31
ClinPred		0.034	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.19

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: rs116262072; hg19: chr7-33427634;