rs765968701
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000349.3(STAR):c.64+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000144 in 1,454,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
STAR
NM_000349.3 splice_donor, intron
NM_000349.3 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.92
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
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.22960372 fraction of the gene.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-38150754-C-A is Pathogenic according to our data. Variant chr8-38150754-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 550998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| STAR | ENST00000276449.9 | c.64+1G>T | splice_donor_variant, intron_variant | 1 | NM_000349.3 | ENSP00000276449.3 | ||||
| STAR | ENST00000520114.1 | n.238+1G>T | splice_donor_variant, intron_variant | 2 | ||||||
| ENSG00000253356 | ENST00000520598.1 | n.99+1915C>A | intron_variant | 4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD3 exomes AF: 0.0000730 AC: 18AN: 246642Hom.: 0 AF XY: 0.0000747 AC XY: 10AN XY: 133846
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1454778Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 724128
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 17, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_000349.2(STAR):c.64+1G>T is a canonical splice variant classified as pathogenic in the context of lipoid congenital adrenal hyperplasia. c.64+1G>T has been observed in cases with relevant disease (PMID: 23859637). Functional assessments of this variant are available in the literature (PMID: 14764819). c.64+1G>T has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, NM_000349.2(STAR):c.64+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change affects a donor splice site in intron 1 of the STAR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in STAR are known to be pathogenic (PMID: 8948562). This variant is present in population databases (rs765968701, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with congenital lipoid adrenal hyperplasia (PMID: 14764819). This variant is also known as IVS+1G>T. ClinVar contains an entry for this variant (Variation ID: 550998). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 14764819). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect with this variant resulting in protein truncation (Gonzalez et al., 2004); This variant is associated with the following publications: (PMID: 31589614, 14764819) - |
STAR-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 15, 2024 | The STAR c.64+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant in the homozygous condition has been reported in one individual with congenital lipoid adrenal hyperplasia (Gonzalez et al 2004. PubMed ID: 14764819). RNA and functional studies suggest that this variant led to abnormal RNA splicing and disrupted the normal protein function (Gonzalez et al 2004. PubMed ID: 14764819). In addition, similar splicing variants (c.64+1G>C; c.64+1G>A) were reported to be pathogenic for 46,XY disorder of sex development/ congenital lipoid adrenal hyperplasia (Baxter. 2015. PubMed ID: 25383892; Zhang. 2021. PubMed ID: 33227378). This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in STAR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at