rs765968701

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.92

Publications

1 publications found

Variant links:

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]

STAR Gene-Disease associations (from GenCC):

congenital lipoid adrenal hyperplasia due to STAR deficency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

STAR links:

ENSG00000253356 (HGNC:):

ENSG00000253356 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.23076923 fraction of the gene.

PP5

Variant 8-38150754-C-A is Pathogenic according to our data. Variant chr8-38150754-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 550998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAR	NM_000349.3 link	c.64+1G>T		splice_donor_variant, intron_variant	Intron 1 of 6	ENST00000276449.9	NP_000340.2	P49675Q6IBK0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
STAR	ENST00000276449.9 link	c.64+1G>T	splice_donor_variant, intron_variant	Intron 1 of 6	1	NM_000349.3	ENSP00000276449.3	P49675
STAR	ENST00000520114.1 link	n.238+1G>T	splice_donor_variant, intron_variant	Intron 1 of 3	2
ENSG00000253356	ENST00000520598.1 link	n.99+1915C>A	intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000730

AC:

AN:

246642

AF XY:

0.0000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1454778

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000623

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000107

AC:

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

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 10, 2021

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 06, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

PhyloP100

6.9

GERP RS

5.2

PromoterAI

-0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.89

Position offset: 2

DS_DL_spliceai

1.0

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over