Variant 18-54329392-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_139171.2(STARD6):c.434G>A(p.Arg145His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,603,516 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

STARD6
NM_139171.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68

Variant links:

Genes affected

STARD6 (HGNC:18066): (StAR related lipid transfer domain containing 6) Cholesterol homeostasis is regulated, at least in part, by sterol regulatory element (SRE)-binding proteins (e.g., SREBP1; MIM 184756) and by liver X receptors (e.g., LXRA; MIM 602423). Upon sterol depletion, LXRs are inactive and SREBPs are cleaved, after which they bind promoter SREs and activate genes involved in cholesterol biosynthesis and uptake. Sterol transport is mediated by vesicles or by soluble protein carriers, such as steroidogenic acute regulatory protein (STAR; MIM 600617). STAR is homologous to a family of proteins containing a 200- to 210-amino acid STAR-related lipid transfer (START) domain, including STARD6 (Soccio et al., 2002 [PubMed 12011452]).[supplied by OMIM, Mar 2008]

STARD6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STARD6	NM_139171.2 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant	7/8	ENST00000307844.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
STARD6	ENST00000307844.4 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant	7/8	1	NM_139171.2	P2
STARD6	ENST00000686109.1 linkuse as main transcript	c.467G>A	p.Arg156His	missense_variant	8/9			A2
STARD6	ENST00000581310.5 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant	8/9	5		P2
STARD6	ENST00000689888.1 linkuse as main transcript	c.*490G>A		3_prime_UTR_variant, NMD_transcript_variant	7/8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242336

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000310

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:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451756

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

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:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74106

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.434G>A (p.R145H) alteration is located in exon 5 (coding exon 5) of the STARD6 gene. This alteration results from a G to A substitution at nucleotide position 434, causing the arginine (R) at amino acid position 145 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Benign

0.70

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

2.9

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.43

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.45

MutPred

0.86

Gain of glycosylation at S141 (P = 0.1165);Gain of glycosylation at S141 (P = 0.1165);

MVP

0.92

MPC

0.74

ClinPred

1.0

GERP RS

5.5

Varity_R

0.70

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over