rs113624356

Variant names:

• chr11-66526181-T-G
• rs113624356
• NM_024649.5:c.1169T>G
• BBS1 p.Met390Arg

Your query was ambiguous. Multiple possible variants found:

• chr11-66526181-T-G
• chr11-66526181-T-C

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PS3PP3PP5_Strong

The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00268 (AC=4,322) in the gnomAD database across 1,614,180 control chromosomes, including 2 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00329. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/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. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M390V: Uncertain_significance (ClinVar VariationId 1979201, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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:63 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]

BBS1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 1

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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)."
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (63/63 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_024649.5. You can select a different transcript below to see updated classification 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	Q8NFJ9-2
	BBS1	ENST00000393994.4	TSL:1	c.782T>G	p.Met261Arg	missense	Exon 9 of 13	ENSP00000377563.2	Q8NFJ9-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00205	AC:312	Hom:0	AN:152210	Cov:32
GnomAD2 exomes	AF: 0.00151	AC:380	Hom:	AN:251388	Cov:
GnomAD4 exome	AF: 0.00274	AC:4010	Hom:2	AN:1461852	Cov:31
GnomAD4 genome	AF: 0.00205	AC:312	Hom:0	AN:152328	Cov:32
TOPMed (Bravo)	AF: 0.00210	AC:556	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00223	AC:1167	Hom:1	AN:522958	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00256	AC:6	Hom:0	AN:2342	Cov:
Denmark Genome	AF: 0.00333	AC:1	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00200	AC:26	Hom:	AN:12990	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
UK10K	AF: 0.00357	AC:27	Hom:	AN:7562	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00207 *	23	11112	0.00199 *	35	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00260	74	28420	0.00239	69	28844
Epi25(Epilepsy)	0.00186	78	41956	0.00232	155	66882
SCHEMA(Schizophrenia)	0.00169	206	121772	0.00248	474	190810

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
27	-	-	Bardet-Biedl syndrome 1 (28)
13	-	-	not provided (13)
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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
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
GPN-Star LLR	N/A	-7.8
GPN-Star score	N/A	7.8
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.081	T
MetaSVM	Uncertain	0.73	D
Mutation Taster	N/A	14/86	disease causing (ClinVar)
MutationAssessor	Uncertain	2.2	M
PhyloP100	Uncertain	4.7
popEVE	Benign	-4.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0080	D
Varity_R	N/A	0.90
VESM-3B	Benign	-15

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2
Splicevardb	N/A	2.0

Showing 3 of 3 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113624356;

hg19: chr11-66293652;

COSMIC: COSV99041500;

COSMIC: COSV99041500;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar