rs765968701

chr8-38150754-C-Achr8-38150754-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_Strong PM2 PP3_Strong PP5_Very_Strong

The NM_000349.3(STAR):c.64+1G>T variant causes a splice donor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing variant, 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAR	NM_000349.3	c.64+1G>T		splice_donor_variant		ENST00000276449.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAR	ENST00000276449.9	c.64+1G>T		splice_donor_variant		1	NM_000349.3	P1
	ENST00000520598.1	n.99+1915C>A		intron_variant, non_coding_transcript_variant		4
STAR	ENST00000520114.1	n.238+1G>T		splice_donor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000730 AC: 18 AN: 246642 Hom.: 0 AF XY: 0.0000747 AC XY: 10 AN XY: 133846

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 SAS 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: 21 AN: 1454778 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 724128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Invitae	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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2022

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 was 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 (http://gnomad.broadinstitute.org/variant/8-38008272-C-A). 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	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs765968701; hg19: chr8-38008272;