rs1417088430

Positions:

• chr8-38145251-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000349.3(STAR):​c.714delA​(p.Lys238fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STAR NM_000349.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.221

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]

ACMG classification

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. Fraction of 0.168 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-38145251-GT-G is Pathogenic according to our data. Variant chr8-38145251-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558171.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.714delA	p.Lys238fs	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.714delA	p.Lys238fs	frameshift_variant	6/7	1	NM_000349.3	ENSP00000276449.3
STAR	ENST00000522050.1	c.584+711delA		intron_variant		5		ENSP00000429009.1
STAR	ENST00000520114.1	n.1848delA		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251482 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2023	Variant summary: STAR c.714delA (p.Lys238AsnfsX83) causes a frameshift which alters the last 48 amino acids of the protein in the START domain (IPR002913) and results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.714delA has been reported in the literature in individuals affected with Congenital Lipoid Adrenal Hyperplasia who were compound heterozygous with another pathogenic variant (Nakae_1997, Qiu_2005, Amano_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that cells transfected with the variant protein had no steroidogenesis enhancing activity (Nakae_2017). The following publications have been ascertained in the context of this evaluation (PMID: 9097960, 15347444, 28546232). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2023

This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change results in a frameshift in the STAR gene (p.Lys238Asnfs*83). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the STAR protein and extend the protein by 34 additional amino acid residues. This frameshift has been observed in individual(s) with congenital lipoid adrenal hyperplasia (PMID: 9077535, 9097960, 10215405, 26827627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 838del. ClinVar contains an entry for this variant (Variation ID: 558171). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects STAR function (PMID: 9097960). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1417088430; hg19: chr8-38002769;