rs77298332

chr11-66529828-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024649.5(BBS1):c.1349G>A(p.Arg450Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,611,024 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R450W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (90 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (103 hom.)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.01

Genes affected

BBS1 (HGNC:966): (Bardet-Biedl syndrome 1) Mutations in this gene have been observed in patients with the major form (type 1) of Bardet-Biedl syndrome. The encoded protein may play a role in eye, limb, cardiac and reproductive system development. [provided by RefSeq, Jul 2008]

ZDHHC24 (HGNC:27387): (zinc finger DHHC-type containing 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029770434).
• BP6: Variant 11-66529828-G-A is Benign according to our data. Variant chr11-66529828-G-A is described in ClinVar as [Benign]. Clinvar id is 194431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-66529828-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS1	NM_024649.5	c.1349G>A	p.Arg450Gln	missense_variant	14/17	ENST00000318312.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12	c.1349G>A	p.Arg450Gln	missense_variant	14/17	1	NM_024649.5	P1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2997 AN: 151886 Hom.: 90 Cov.: 31

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0178

GnomAD3 exomes AF: 0.00540 AC: 1341 AN: 248268 Hom.: 49 AF XY: 0.00382 AC XY: 513 AN XY: 134468

Gnomad AFR exome AF: 0.0710

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00203 AC: 2968 AN: 1459020 Hom.: 103 Cov.: 32 AF XY: 0.00172 AC XY: 1247 AN XY: 725982

Gnomad4 AFR exome AF: 0.0703

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.0198 AC: 3011 AN: 152004 Hom.: 90 Cov.: 31 AF XY: 0.0189 AC XY: 1405 AN XY: 74300

Gnomad4 AFR AF: 0.0685

Gnomad4 AMR AF: 0.00779

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.00389 Hom.: 33

Bravo AF: 0.0229

ESP6500AA AF: 0.0668 AC: 294

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00664 AC: 806

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -

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	0.081
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.057
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	D;D;N;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.093	T;T;T;T
Polyphen		0.17, 0.60	.;B;P;.
Vest4		0.21
MVP		0.92
MPC		0.18
ClinPred		0.0090	T
GERP RS		3.5
Varity_R		0.27
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs77298332; hg19: chr11-66297299;