chr7-33533991-T-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP3BP4_StrongBP6BS1
The NM_198428.3(BBS9):c.2336T>A(p.Leu779Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,614,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_198428.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BBS9 | NM_198428.3 | c.2336T>A | p.Leu779Gln | missense_variant | Exon 21 of 23 | ENST00000242067.11 | NP_940820.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00171 AC: 260AN: 152238Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000477 AC: 120AN: 251484Hom.: 1 AF XY: 0.000375 AC XY: 51AN XY: 135918
GnomAD4 exome AF: 0.000164 AC: 240AN: 1461894Hom.: 0 Cov.: 30 AF XY: 0.000143 AC XY: 104AN XY: 727248
GnomAD4 genome AF: 0.00171 AC: 260AN: 152356Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131AN XY: 74510
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Reported in the heterozygous state in an individual with Bardet-Biedl syndrome (BBS) who was not found to have a second BBS9 variant but did harbor a variant in another BBS-related gene; however, familial segregation information was not provided for either variant (PMID: 21052717); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as p.L781Q; This variant is associated with the following publications: (PMID: 21052717) -
not specified Uncertain:1
DNA sequence analysis of the BBS9 gene demonstrated a sequence change, c.2336T>A, in exon 21 that results in an amino acid change, p.Leu779Gln. This sequence change has been described in the gnomAD database with a frequency of 0.66% in the African/African American subpopulation and includes one individual homozygous for this variant (dbSNP rs142434516). The p.Leu779Gln change affects a highly conserved amino acid residue located in a domain of the BBS9 protein that is not known to be functional. The p.Leu779Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in an individual with Bardet-Biedl syndrome in the heterozygous state, however a second variant in BBS9 or another BBS-related gene was not identified (PMID: 21052717). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu779Gln change remains unknown at this time. -
Bardet-Biedl syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at