rs201872547

chr11-66523808-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024649.5(BBS1):c.1036G>A(p.Val346Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,613,612 control chromosomes in the GnomAD database, including 9 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V346V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (9 hom.)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.33

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009018987).
• BP6: Variant 11-66523808-G-A is Benign according to our data. Variant chr11-66523808-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 305465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS1	NM_024649.5	c.1036G>A	p.Val346Ile	missense_variant	11/17	ENST00000318312.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12	c.1036G>A	p.Val346Ile	missense_variant	11/17	1	NM_024649.5	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000942 AC: 236 AN: 250530 Hom.: 4 AF XY: 0.00111 AC XY: 150 AN XY: 135512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000455 AC: 665 AN: 1461284 Hom.: 9 Cov.: 31 AF XY: 0.000619 AC XY: 450 AN XY: 726942

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00693

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74490

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.97	.;D;D
Vest4		0.36
MVP		0.81
MPC		0.57
ClinPred		0.043	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201872547; hg19: chr11-66291279; COSMIC: COSV59149934; COSMIC: COSV59149934;