11-66521275-C-A

Position:

• chr11-66521275-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024649.5(BBS1):​c.729C>A​(p.Ser243Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S243T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS1 NM_024649.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.370

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]

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1724751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS1	NM_024649.5	c.729C>A	p.Ser243Arg	missense_variant	9/17	ENST00000318312.12	NP_078925.3
ZDHHC24	NM_001348571.2	c.*213G>T		3_prime_UTR_variant	5/5		NP_001335500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS1	ENST00000318312.12	c.729C>A	p.Ser243Arg	missense_variant	9/17	1	NM_024649.5	ENSP00000317469	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BBS1 protein function. ClinVar contains an entry for this variant (Variation ID: 1398377). This variant has not been reported in the literature in individuals affected with BBS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 243 of the BBS1 protein (p.Ser243Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	6.6
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	.;T;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.89	D;D;D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.3	.;L;.;.
MutationTaster	Benign	0.65	D;D;D;N;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.44	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.66, 0.89	.;P;.;P
Vest4		0.55
MutPred		0.34		.;Gain of methylation at S243 (P = 0.0441);.;.;
MVP		0.73
MPC		0.26
ClinPred		0.34	T
GERP RS		0.21
Varity_R		0.056
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1180861221; hg19: chr11-66288746;