chr11-66526181-T-G

Variant names:

• chr11-66526181-T-G
• rs113624356
• NM_024649.5:c.1169T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 14P and 2B. PS3 PM1 PP5_Very_Strong BP4 BS2_Supporting

The NM_024649.5(BBS1):​c.1169T>G​(p.Met390Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,614,180 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000373275: A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID:18032602)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M390V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (2 hom.)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:60 O:2
• Conservation: PhyloP100: 4.70
• Publications: 206 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000373275: A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID: 18032602).; SCV001573536: Well-established functional studies show a deleterious effect (PS3).; SCV002058656: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12118255, 12677556, 22940089, 23143442).; SCV002503686: A knock-in mouse model homozygous for p.Met390Arg has cilia defects, and recapitulates aspects of the human BBS phenotype, including retinal degeneration, male infertility, and obesity (PMID: 18032602), and partial rescue (hypomorph) was demonstrated in a zebrafish assay (PMID: 20498079).; SCV000329106: Published functional studies demonstrate a damaging effect as mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007);; SCV000253934: Experimental studies have shown that this missense change affects BBS1 function (PMID: 15314642, 18032602, 20498079).; SCV000699512: An in vivo BBS mouse model shows that mice homozygous for the M390R mutation recapitulate aspects of the human phenotype, including retinal degeneration, male infertility, and obesity (Davis_PNAS_2007).; SCV000712198: Animal models in mice have shown that this variant causes Bardet-Biedl syndrome (Davis 2007).; SCV003539679: Functional studies in zebrafish lacking BBS1 and co-injected with wildtype mRNA and this mutation demonstrated only a partial rescue, consistent with a possible hypomorphic effect of this variant (Zaghloul, 2010).; SCV004120938: "In vivo and in vitro studies suggest that this variant impacts protein function (Davis et al. 2007. PubMed ID: 18032602; Zaghloul et al. 2010. PubMed ID: 20498079)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_024649.5
• PP5: Variant 11-66526181-T-G is Pathogenic according to our data. Variant chr11-66526181-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08079672). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1169T>G	p.Met390Arg	missense	Exon 12 of 17	NP_078925.3
	ZDHHC24	NM_001348571.2		c.*21+755A>C		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.1169T>G	p.Met390Arg	missense	Exon 12 of 17	ENSP00000317469.7	Q8NFJ9-1
	ENSG00000256349	ENST00000419755.3	TSL:2	c.1280T>G	p.Met427Arg	missense	Exon 12 of 17	ENSP00000398526.3
	BBS1	ENST00000393994.4	TSL:1	c.782T>G	p.Met261Arg	missense	Exon 9 of 13	ENSP00000377563.2	Q8NFJ9-3

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00151 AC: 380 AN: 251388 AF XY: 0.00163

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00274 AC: 4010 AN: 1461852 Hom.: 2 Cov.: 31 AF XY: 0.00268 AC XY: 1952 AN XY: 727236

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.00101 AC: 45 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000786 AC: 42 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00338 AC: 3756 AN: 1111982

Other (OTH) AF: 0.00250 AC: 151 AN: 60394

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74488

African (AFR) AF: 0.000890 AC: 37 AN: 41580

American (AMR) AF: 0.00262 AC: 40 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00210

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
25	-	-	Bardet-Biedl syndrome 1 (26)
12	-	-	not provided (12)
10	-	-	Bardet-Biedl syndrome (11)
4	-	-	Retinal dystrophy (4)
3	-	-	Retinitis pigmentosa (3)
1	-	-	BBS1-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Retinal disorder (1)
1	-	-	See cases (1)
1	-	-	Severe early-childhood-onset retinal dystrophy (1)
1	-	-	Usher syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.081	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.73	P
Vest4		0.98
MVP		0.94
MPC		0.38
ClinPred		0.070	T
GERP RS		4.5
Varity_R		0.90
gMVP		0.95
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs113624356; hg19: chr11-66293652; COSMIC: COSV99041500; COSMIC: COSV99041500;