rs9769506

Variant names:

• chr7-155308145-C-A
• rs9769506
• NM_005542.6:c.805-96C>A

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
INSIG1	NM_005542.6	c.805-96C>A		intron_variant	Intron 5 of 5	ENST00000340368.9	NP_005533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSIG1	ENST00000340368.9	c.805-96C>A		intron_variant	Intron 5 of 5	1	NM_005542.6	ENSP00000344741.4
INSIG1	ENST00000476756.1	c.600-96C>A		intron_variant	Intron 5 of 5	2		ENSP00000420198.1
INSIG1	ENST00000344756.8	c.420-96C>A		intron_variant	Intron 5 of 5	5		ENSP00000340010.4
INSIG1	ENST00000342407.5	c.*18-96C>A		intron_variant	Intron 3 of 3	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 AC: 7157 AN: 13436

Gnomad4 AMR exome AF: 0.503 AC: 12330 AN: 24500

Gnomad4 ASJ exome AF: 0.418 AC: 6260 AN: 14976

Gnomad4 EAS exome AF: 0.00747 AC: 242 AN: 32416

Gnomad4 SAS exome AF: 0.299 AC: 14232 AN: 47526

Gnomad4 FIN exome AF: 0.512 AC: 16522 AN: 32268

Gnomad4 NFE exome AF: 0.543 AC: 169932 AN: 312856

Gnomad4 Remaining exome AF: 0.478 AC: 13201 AN: 27632

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 AC: 0.543073 AN: 0.543073

Gnomad4 AMR AF: 0.533 AC: 0.532748 AN: 0.532748

Gnomad4 ASJ AF: 0.423 AC: 0.422677 AN: 0.422677

Gnomad4 EAS AF: 0.00911 AC: 0.00910853 AN: 0.00910853

Gnomad4 SAS AF: 0.268 AC: 0.268303 AN: 0.268303

Gnomad4 FIN AF: 0.492 AC: 0.492118 AN: 0.492118

Gnomad4 NFE AF: 0.543 AC: 0.543419 AN: 0.543419

Gnomad4 OTH AF: 0.485 AC: 0.485294 AN: 0.485294

Alfa AF: 0.528 Hom.: 35689

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
Mutation Taster		=100/0	polymorphism (auto)

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;