11-66521262-G-C

Variant names:

• chr11-66521262-G-C
• rs10896125
• ENST00000526986.5:c.*226C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024649.5(BBS1):​c.724-8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,611,188 control chromosomes in the GnomAD database, including 47,428 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4629 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42799 hom.)
• Consequence: BBS1 NM_024649.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005736
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.690
• Publications: 19 publications found

Genes affected

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]

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]

BBS1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-66521262-G-C is Benign according to our data. Variant chr11-66521262-G-C is described in ClinVar as Benign. ClinVar VariationId is 96131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 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.724-8G>C		splice_region intron	N/A	NP_078925.3
	ZDHHC24	NM_001348571.2		c.*226C>G		3_prime_UTR	Exon 5 of 5	NP_001335500.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC24	ENST00000526986.5	TSL:1	c.*226C>G		3_prime_UTR	Exon 5 of 5	ENSP00000431321.1
	BBS1	ENST00000318312.12	TSL:1 MANE Select	c.724-8G>C		splice_region intron	N/A	ENSP00000317469.7
	ENSG00000256349	ENST00000419755.3	TSL:2	c.835-8G>C		splice_region intron	N/A	ENSP00000398526.3

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36436 AN: 152010 Hom.: 4621 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.232 AC: 58276 AN: 251346 AF XY: 0.233

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.238 AC: 347625 AN: 1459060 Hom.: 42799 Cov.: 30 AF XY: 0.238 AC XY: 172899 AN XY: 726058

African (AFR) AF: 0.226 AC: 7558 AN: 33428

American (AMR) AF: 0.149 AC: 6678 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4379 AN: 26116

East Asian (EAS) AF: 0.261 AC: 10346 AN: 39686

South Asian (SAS) AF: 0.215 AC: 18532 AN: 86198

European-Finnish (FIN) AF: 0.373 AC: 19928 AN: 53402

Middle Eastern (MID) AF: 0.136 AC: 776 AN: 5714

European-Non Finnish (NFE) AF: 0.240 AC: 265737 AN: 1109504

Other (OTH) AF: 0.227 AC: 13691 AN: 60292

GnomAD4 genome AF: 0.240 AC: 36469 AN: 152128 Hom.: 4629 Cov.: 32 AF XY: 0.244 AC XY: 18147 AN XY: 74356

African (AFR) AF: 0.230 AC: 9550 AN: 41508

American (AMR) AF: 0.181 AC: 2773 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 522 AN: 3468

East Asian (EAS) AF: 0.268 AC: 1387 AN: 5168

South Asian (SAS) AF: 0.202 AC: 972 AN: 4820

European-Finnish (FIN) AF: 0.388 AC: 4099 AN: 10564

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16472 AN: 68004

Other (OTH) AF: 0.200 AC: 423 AN: 2110

Alfa AF: 0.194 Hom.: 1044

Bravo AF: 0.223

Asia WGS AF: 0.245 AC: 850 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.229

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Bardet-Biedl syndrome 1 (7)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0020
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: rs10896125; hg19: chr11-66288733; COSMIC: COSV59147680; COSMIC: COSV59147680;