11-66510662-G-A

Variant names:

• chr11-66510662-G-A
• rs1855918305
• NM_024649.5:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_024649.5(BBS1):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS1 NM_024649.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.55
• Publications: 0 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]

BBS1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• BBS1-related ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 17 pathogenic variants. Next in-frame start position is after 31 codons. Genomic position: 66511056. Lost 0.051 part of the original CDS.
• PS1: Another start lost variant in NM_024649.5 (BBS1) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-66510662-G-A is Pathogenic according to our data. Variant chr11-66510662-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2057607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3G>A	p.Met1?	start_lost	Exon 1 of 17	NP_078925.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS1	ENST00000318312.12	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 17	ENSP00000317469.7	Q8NFJ9-1
	BBS1	ENST00000393994.4	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000377563.2	Q8NFJ9-3
	ENSG00000256349	ENST00000419755.3	TSL:2	c.159-351G>A		intron	N/A	ENSP00000398526.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bardet-Biedl syndrome (1)
1	-	-	Bardet-Biedl syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.6
PROVEAN	Benign	-0.96	N
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.97
MutPred		0.97		Gain of sheet (P = 0.0477)
MVP		0.95
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.98	Under-expression
Varity_R		0.96
gMVP		0.51
Mutation Taster		=9/191	disease causing

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: rs1855918305; hg19: chr11-66278133;