chr11-66526181-T-C

Variant names:

• chr11-66526181-T-C
• rs113624356
• NM_024649.5:c.1169T>C
• BBS1 p.Met390Thr

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_024649.5(BBS1):c.1169T>C (p.Met390Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000899, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.M390R: Pathogenic/Likely_pathogenic (ClinVar VariationId 12143, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M390V: Uncertain_significance (ClinVar VariationId 1979201, 1 star)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70
• Publications: 192 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): (zDHHC palmitoyltransferase 24) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in protein targeting to membrane. Predicted to be located in membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Jul 2025]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AR gene (base 0.001, raised to 0.00268 by highest known P/LP ClinVar AF 0.00268) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.M390R: Pathogenic/Likely_pathogenic (ClinVar VariationId 12143, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.M390V: Uncertain_significance (ClinVar VariationId 1979201, 1 star)

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>C p.Met390Thr	missense	Exon 12 of 17	Prot: NP_078925.3
	ZDHHC24 NM_001348571.2		c.*21+755A>G	intron	Intron 4 of 4	Prot: NP_001335500.1 UniProt:

BBS1 NM_024649.5

MANE Select

HGVSc / HGVSpc.1169T>Cp.Met390Thr

Exon rankExon 12 of 17

missense

Prot: NP_078925.3

ZDHHC24 NM_001348571.2

HGVSc / HGVSpc.*21+755A>G

Exon rankIntron 4 of 4

intron

Prot: NP_001335500.1UniProt: E9PLR9

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BBS1 ENST00000318312.12	TSL:1MANE Select	c.1169T>C p.Met390Thr	missense	Exon 12 of 17	Prot: ENSP00000317469.7 UniProt:
	ENSG00000256349 ENST00000419755.3	TSL:2	c.1280T>C p.Met427Thr	missense	Exon 12 of 17	Prot: ENSP00000398526.3 UniProt:
	BBS1 ENST00000393994.4	TSL:1	c.782T>C p.Met261Thr	missense	Exon 9 of 13	Prot: ENSP00000377563.2 UniProt:

BBS1 ENST00000318312.12

TSL:1MANE Select

HGVSc / HGVSpc.1169T>Cp.Met390Thr

Exon rankExon 12 of 17

missense

Prot: ENSP00000317469.7UniProt: Q8NFJ9-1

ENSG00000256349 ENST00000419755.3

TSL:2

HGVSc / HGVSpc.1280T>Cp.Met427Thr

Exon rankExon 12 of 17

missense

Prot: ENSP00000398526.3UniProt: Q8NFJ9-2

BBS1 ENST00000393994.4

TSL:1

HGVSc / HGVSpc.782T>Cp.Met261Thr

Exon rankExon 9 of 13

missense

Prot: ENSP00000377563.2UniProt: 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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 6.84e-7	AC:1	Hom:0	AN:1461860	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.047
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.027
GPN-Star LLR	N/A	-5.5
GPN-Star score	N/A	5.5
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.18	T
Mutation Taster	N/A	27/73	disease causing
MutationAssessor	Benign	1.8	L
PhyloP100	Uncertain	4.7
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.34
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Varity_R	N/A	0.50
VESM-3B	Benign	-9.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs113624356;

hg19: chr11-66293652;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar