8-38146068-C-T

Variant names:

• chr8-38146068-C-T
• rs104894086
• NM_000349.3:c.545G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000349.3(STAR):​c.545G>A​(p.Arg182His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,874 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000950951: Experimental studies have shown that this missense change affects STAR function (PMID:15546900)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: STAR NM_000349.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.32
• Publications: 35 publications found

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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000950951: Experimental studies have shown that this missense change affects STAR function (PMID: 15546900).; SCV002525604: Experimental studies have demonstrated that the p.Arg182His change impairs protein function (PMID: 15546900).; SCV005201955: Published functional studies demonstrate a damaging effect on protein activity (PMID: 17301050, 15546900)
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000349.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-38146069-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3251758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 8-38146068-C-T is Pathogenic according to our data. Variant chr8-38146068-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000349.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAR	NM_000349.3	MANE Select	c.545G>A	p.Arg182His	missense	Exon 5 of 7	NP_000340.2	Q6IBK0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAR	ENST00000276449.9	TSL:1 MANE Select	c.545G>A	p.Arg182His	missense	Exon 5 of 7	ENSP00000276449.3	P49675
	STAR	ENST00000971759.1		c.536G>A	p.Arg179His	missense	Exon 5 of 7	ENSP00000641818.1
	STAR	ENST00000522050.1	TSL:5	c.479G>A	p.Arg160His	missense	Exon 4 of 5	ENSP00000429009.1	H0YB94

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Congenital lipoid adrenal hyperplasia due to STAR deficency (5)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		1.0		Loss of MoRF binding (P = 0.0279)
MVP		0.97
MPC		0.93
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs104894086; hg19: chr8-38003586;