8-38144359-G-C

Variant names:

• chr8-38144359-G-C
• rs104894085
• NM_000349.3:c.772C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000349.3(STAR):​c.772C>G​(p.Gln258Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAR NM_000349.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71
• Publications: 0 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]

ASH2L (HGNC:744): (ASH2 like, histone lysine methyltransferase complex subunit) Enables beta-catenin binding activity and transcription cis-regulatory region binding activity. Contributes to histone methyltransferase activity (H3-K4 specific). Involved in histone H3-K4 methylation; positive regulation of cell population proliferation; and response to estrogen. Acts upstream of or within cellular response to DNA damage stimulus. Located in nucleus. Part of MLL3/4 complex and Set1C/COMPASS complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a chain Steroidogenic acute regulatory protein, mitochondrial (size 221) in uniprot entity STAR_HUMAN there are 21 pathogenic changes around while only 4 benign (84%) in NM_000349.3
• PM2: Very rare variant in population databases, with high coverage

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.772C>G	p.Gln258Glu	missense	Exon 7 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.772C>G	p.Gln258Glu	missense	Exon 7 of 7	ENSP00000276449.3	P49675
	STAR	ENST00000971759.1		c.763C>G	p.Gln255Glu	missense	Exon 7 of 7	ENSP00000641818.1
	STAR	ENST00000927192.1		c.493C>G	p.Gln165Glu	missense	Exon 5 of 5	ENSP00000597251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.10	B
Vest4		0.37
MutPred		0.66		Gain of ubiquitination at K253 (P = 0.0696)
MVP		0.89
MPC		0.25
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.85
Mutation Taster		=61/39	polymorphism

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: rs104894085; hg19: chr8-38001877;