11-66529892-C-T

Variant names:

• chr11-66529892-C-T
• rs3816492
• NM_024649.5:c.1413C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024649.5(BBS1):​c.1413C>T​(p.Leu471Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,607,944 control chromosomes in the GnomAD database, including 43,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L471L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3319 hom., cov: 31)
  • Exomes 𝑓: 0.23 (40111 hom.)
• Consequence: BBS1 NM_024649.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.745
• Publications: 38 publications found

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]

ENSG00000256349 (HGNC:):

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-66529892-C-T is Benign according to our data. Variant chr11-66529892-C-T is described in ClinVar as Benign. ClinVar VariationId is 261747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.745 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024649.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS1	NM_024649.5	MANE Select	c.1413C>T	p.Leu471Leu	synonymous	Exon 14 of 17	NP_078925.3
	ZDHHC24	NM_001348571.2		c.560-404G>A		intron	N/A	NP_001335500.1	E9PLR9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS1	ENST00000318312.12	TSL:1 MANE Select	c.1413C>T	p.Leu471Leu	synonymous	Exon 14 of 17	ENSP00000317469.7	Q8NFJ9-1
	ENSG00000256349	ENST00000419755.3	TSL:2	c.1524C>T	p.Leu508Leu	synonymous	Exon 14 of 17	ENSP00000398526.3
	BBS1	ENST00000393994.4	TSL:1	c.1026C>T	p.Leu342Leu	synonymous	Exon 11 of 13	ENSP00000377563.2	Q8NFJ9-3

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27417 AN: 151950 Hom.: 3314 Cov.: 31

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.203 AC: 49593 AN: 244460 AF XY: 0.210

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.228 AC: 332334 AN: 1455876 Hom.: 40111 Cov.: 40 AF XY: 0.229 AC XY: 165949 AN XY: 724504

African (AFR) AF: 0.0347 AC: 1162 AN: 33476

American (AMR) AF: 0.136 AC: 6080 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4360 AN: 26122

East Asian (EAS) AF: 0.132 AC: 5232 AN: 39678

South Asian (SAS) AF: 0.207 AC: 17873 AN: 86234

European-Finnish (FIN) AF: 0.372 AC: 17819 AN: 47842

Middle Eastern (MID) AF: 0.130 AC: 748 AN: 5768

European-Non Finnish (NFE) AF: 0.240 AC: 266560 AN: 1111772

Other (OTH) AF: 0.207 AC: 12500 AN: 60332

GnomAD4 genome AF: 0.180 AC: 27429 AN: 152068 Hom.: 3319 Cov.: 31 AF XY: 0.186 AC XY: 13815 AN XY: 74304

African (AFR) AF: 0.0429 AC: 1783 AN: 41518

American (AMR) AF: 0.156 AC: 2386 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3472

East Asian (EAS) AF: 0.131 AC: 678 AN: 5162

South Asian (SAS) AF: 0.194 AC: 934 AN: 4810

European-Finnish (FIN) AF: 0.387 AC: 4086 AN: 10556

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16443 AN: 67962

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.210 Hom.: 9989

Bravo AF: 0.155

Asia WGS AF: 0.173 AC: 602 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.229

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Bardet-Biedl syndrome 1 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.83
DANN	Benign	0.92
PhyloP100		-0.74
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3816492; hg19: chr11-66297363; COSMIC: COSV59147234; COSMIC: COSV59147234;