rs757367795
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000276449.9(STAR):βc.695delβ(p.Gly232GlufsTer89) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000048 ( 0 hom. )
Consequence
STAR
ENST00000276449.9 frameshift
ENST00000276449.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.45
Genes affected
STAR (HGNC:11359): (steroidogenic acute regulatory protein) The protein encoded by this gene plays a key role in the acute regulation of steroid hormone synthesis by enhancing the conversion of cholesterol into pregnenolone. This protein permits the cleavage of cholesterol into pregnenolone by mediating the transport of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane. Mutations in this gene are a cause of congenital lipoid adrenal hyperplasia (CLAH), also called lipoid CAH. A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-38145270-TC-T is Pathogenic according to our data. Variant chr8-38145270-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STAR | NM_000349.3 | c.695del | p.Gly232GlufsTer89 | frameshift_variant | 6/7 | ENST00000276449.9 | NP_000340.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STAR | ENST00000276449.9 | c.695del | p.Gly232GlufsTer89 | frameshift_variant | 6/7 | 1 | NM_000349.3 | ENSP00000276449 | P1 | |
STAR | ENST00000522050.1 | c.586+692del | intron_variant | 5 | ENSP00000429009 | |||||
STAR | ENST00000520114.1 | n.1829del | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461872Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 727234
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 06, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 07, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the STAR protein in which other variant(s) (p.Gln258*) have been determined to be pathogenic (PMID: 8948562, 9097960, 22028173, 28467518). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 558205). This premature translational stop signal has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 26827627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs757367795, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gly232Glufs*89) in the STAR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the STAR protein. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at