rs9770068

Positions:

• chr7-155308052-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005542.6(INSIG1):​c.805-189T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 151,978 control chromosomes in the GnomAD database, including 24,669 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24669 hom., cov: 32)
• Consequence: INSIG1 NM_005542.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02

Genes affected

INSIG1 (HGNC:6083): (insulin induced gene 1) This gene encodes an endoplasmic reticulum membrane protein that regulates cholesterol metabolism, lipogenesis, and glucose homeostasis. The encoded protein has six transmembrane helices which contain an effector protein binding site. It binds the sterol-sensing domains of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), and is essential for the sterol-mediated trafficking of these two proteins. It promotes the endoplasmic reticulum retention of SCAP and the ubiquitin-mediated degradation of HMG-CoA reductase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSIG1	NM_005542.6	c.805-189T>C		intron_variant		ENST00000340368.9	NP_005533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSIG1	ENST00000340368.9	c.805-189T>C		intron_variant		1	NM_005542.6	ENSP00000344741.4
INSIG1	ENST00000476756.1	c.600-189T>C		intron_variant		2		ENSP00000420198.1
INSIG1	ENST00000344756.8	c.420-189T>C		intron_variant		5		ENSP00000340010.4
INSIG1	ENST00000342407.5	c.*18-189T>C		intron_variant		2		ENSP00000344035.5

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84483 AN: 151860 Hom.: 24640 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.00888

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.530

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.556 AC: 84558 AN: 151978 Hom.: 24669 Cov.: 32 AF XY: 0.549 AC XY: 40803 AN XY: 74280

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.562

Gnomad4 ASJ AF: 0.440

Gnomad4 EAS AF: 0.00909

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.598

Gnomad4 OTH AF: 0.524

Alfa AF: 0.588 Hom.: 3880

Bravo AF: 0.556

Asia WGS AF: 0.171 AC: 595 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.50
DANN	Benign	0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs9770068; hg19: chr7-155099762;