NM_005542.6:c.805-96C>A

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
• Publications: 17 publications found

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005542.6. 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
	INSIG1	NM_005542.6	MANE Select	c.805-96C>A		intron	N/A	NP_005533.2
	INSIG1	NM_001346590.2		c.876-96C>A		intron	N/A	NP_001333519.1	A4D2M9
	INSIG1	NM_001346591.2		c.876-96C>A		intron	N/A	NP_001333520.1	A4D2M9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSIG1	ENST00000340368.9	TSL:1 MANE Select	c.805-96C>A		intron	N/A	ENSP00000344741.4	O15503-1
	INSIG1	ENST00000885536.1		c.835-96C>A		intron	N/A	ENSP00000555595.1
	INSIG1	ENST00000885537.1		c.823-96C>A		intron	N/A	ENSP00000555596.1

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

African (AFR) AF: 0.533 AC: 7157 AN: 13436

American (AMR) AF: 0.503 AC: 12330 AN: 24500

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 6260 AN: 14976

East Asian (EAS) AF: 0.00747 AC: 242 AN: 32416

South Asian (SAS) AF: 0.299 AC: 14232 AN: 47526

European-Finnish (FIN) AF: 0.512 AC: 16522 AN: 32268

Middle Eastern (MID) AF: 0.466 AC: 1196 AN: 2564

European-Non Finnish (NFE) AF: 0.543 AC: 169932 AN: 312856

Other (OTH) 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

African (AFR) AF: 0.543 AC: 22493 AN: 41418

American (AMR) AF: 0.533 AC: 8134 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1465 AN: 3466

East Asian (EAS) AF: 0.00911 AC: 47 AN: 5160

South Asian (SAS) AF: 0.268 AC: 1290 AN: 4808

European-Finnish (FIN) AF: 0.492 AC: 5182 AN: 10530

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.543 AC: 36909 AN: 67920

Other (OTH) AF: 0.485 AC: 1023 AN: 2108

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.46
PhyloP100		0.033
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

Other links and lift over

dbSNP: rs9769506; hg19: chr7-155099855;