rs9769506

Positions:

• chr7-155308145-C-A

Variant summary

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

The NM_005542.6(INSIG1):​c.805-96C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 660,052 control chromosomes in the GnomAD database, including 83,361 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 0.51 (20651 hom., cov: 31)
  • Exomes 𝑓: 0.47 (62710 hom.)
• Consequence: INSIG1 NM_005542.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330

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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSIG1	NM_005542.6	c.805-96C>A		intron_variant		ENST00000340368.9	NP_005533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSIG1	ENST00000340368.9	c.805-96C>A		intron_variant		1	NM_005542.6	ENSP00000344741.4
INSIG1	ENST00000476756.1	c.600-96C>A		intron_variant		2		ENSP00000420198.1
INSIG1	ENST00000344756.8	c.420-96C>A		intron_variant		5		ENSP00000340010.4
INSIG1	ENST00000342407.5	c.*18-96C>A		intron_variant		2		ENSP00000344035.5

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77299 AN: 151762 Hom.: 20625 Cov.: 31

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.00889

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.491

GnomAD4 exome AF: 0.474 AC: 241072 AN: 508174 Hom.: 62710 AF XY: 0.468 AC XY: 126245 AN XY: 269828

Gnomad4 AFR exome AF: 0.533

Gnomad4 AMR exome AF: 0.503

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.00747

Gnomad4 SAS exome AF: 0.299

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.509 AC: 77366 AN: 151878 Hom.: 20651 Cov.: 31 AF XY: 0.501 AC XY: 37184 AN XY: 74214

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.423

Gnomad4 EAS AF: 0.00911

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.492

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.485

Alfa AF: 0.527 Hom.: 28031

Bravo AF: 0.514

Asia WGS AF: 0.160 AC: 558 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs9769506; hg19: chr7-155099855;