rs551783234
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000349.3(STAR):āc.779T>Cā(p.Leu260Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,607,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000062 ( 0 hom. )
Consequence
STAR
NM_000349.3 missense
NM_000349.3 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 8.61
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 16 ACMG points.
PM1
?
In a helix (size 21) in uniprot entity STAR_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000349.3
PM2
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Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
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Variant 8-38144352-A-G is Pathogenic according to our data. Variant chr8-38144352-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STAR | NM_000349.3 | c.779T>C | p.Leu260Pro | missense_variant | 7/7 | ENST00000276449.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STAR | ENST00000276449.9 | c.779T>C | p.Leu260Pro | missense_variant | 7/7 | 1 | NM_000349.3 | P1 | |
STAR | ENST00000522050.1 | c.622T>C | p.Cys208Arg | missense_variant | 5/5 | 5 | |||
STAR | ENST00000520114.1 | n.2748T>C | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000126 AC: 3AN: 237740Hom.: 0 AF XY: 0.00000779 AC XY: 1AN XY: 128402
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GnomAD4 exome AF: 0.00000618 AC: 9AN: 1455402Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3AN XY: 723328
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GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152360Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74506
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 29, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 19, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 25, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 260 of the STAR protein (p.Leu260Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 15985476, 20444910). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553482). 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 expected to disrupt STAR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAR function (PMID: 15985476, 20444910). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0486);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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