11-66521271-T-A

Position:

• chr11-66521271-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024649.5(BBS1):​c.725T>A​(p.Met242Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. M242I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS1 NM_024649.5 missense, splice_region
• Scores: Splicing: ADA: 0.3783
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS1	NM_024649.5	c.725T>A	p.Met242Lys	missense_variant, splice_region_variant	9/17	ENST00000318312.12
ZDHHC24	NM_001348571.2	c.*217A>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS1	ENST00000318312.12	c.725T>A	p.Met242Lys	missense_variant, splice_region_variant	9/17	1	NM_024649.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.725T>A (p.M242K) alteration is located in exon 9 (coding exon 9) of the BBS1 gene. This alteration results from a T to A substitution at nucleotide position 725, causing the methionine (M) at amino acid position 242 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.6	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D;D;D;N
REVEL	Pathogenic	0.80
Sift	Benign	0.035	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		0.89, 0.98	.;P;.;D
Vest4		0.91
MutPred		0.51		.;Gain of solvent accessibility (P = 0.0281);.;.;
MVP		0.95
MPC		0.30
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66288742;