rs372939761

Variant names:

• chr11-66521340-C-A
• rs372939761
• NM_024649.5:c.794C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-66521340-C-A
• chr11-66521340-C-G
• chr11-66521340-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_024649.5(BBS1):​c.794C>A​(p.Ala265Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A265S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.22
• 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]

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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-66521340-C-A is Pathogenic according to our data. Variant chr11-66521340-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412285.

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.794C>A	p.Ala265Glu	missense	Exon 9 of 17	NP_078925.3
	ZDHHC24	NM_001348571.2		c.*148G>T		3_prime_UTR	Exon 5 of 5	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.794C>A	p.Ala265Glu	missense	Exon 9 of 17	ENSP00000317469.7	Q8NFJ9-1
	ENSG00000256349	ENST00000419755.3	TSL:2	c.905C>A	p.Ala302Glu	missense	Exon 9 of 17	ENSP00000398526.3
	ZDHHC24	ENST00000526986.5	TSL:1	c.*148G>T		3_prime_UTR	Exon 5 of 5	ENSP00000431321.1	E9PLR9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.013	D
Polyphen		0.82	P
Vest4		0.82
MutPred		0.43		Gain of relative solvent accessibility (P = 0.09)
MVP		0.93
MPC		0.71
ClinPred		0.86	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.89
Mutation Taster		=55/45	polymorphism

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: rs372939761; hg19: chr11-66288811;