7-155307946-A-G

Variant names:

• chr7-155307946-A-G
• rs9769826
• NM_005542.6:c.805-295A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005542.6(INSIG1):​c.805-295A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 151,632 control chromosomes in the GnomAD database, including 27,810 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 0.59 (27810 hom., cov: 32)
• Consequence: INSIG1 NM_005542.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSIG1	NM_005542.6	c.805-295A>G		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.805-295A>G		intron_variant	Intron 5 of 5	1	NM_005542.6	ENSP00000344741.4
INSIG1	ENST00000476756.1	c.600-295A>G		intron_variant	Intron 5 of 5	2		ENSP00000420198.1
INSIG1	ENST00000344756.8	c.420-295A>G		intron_variant	Intron 5 of 5	5		ENSP00000340010.4
INSIG1	ENST00000342407.5	c.*18-295A>G		intron_variant	Intron 3 of 3	2		ENSP00000344035.5

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90078 AN: 151514 Hom.: 27777 Cov.: 32

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.563

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

GnomAD4 genome AF: 0.595 AC: 90153 AN: 151632 Hom.: 27810 Cov.: 32 AF XY: 0.588 AC XY: 43585 AN XY: 74082

African (AFR) AF: 0.682 AC: 28191 AN: 41336

American (AMR) AF: 0.594 AC: 9054 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1569 AN: 3466

East Asian (EAS) AF: 0.126 AC: 652 AN: 5176

South Asian (SAS) AF: 0.318 AC: 1533 AN: 4814

European-Finnish (FIN) AF: 0.591 AC: 6190 AN: 10478

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.604 AC: 40928 AN: 67794

Other (OTH) AF: 0.556 AC: 1174 AN: 2112

Alfa AF: 0.605 Hom.: 20910

Bravo AF: 0.600

Asia WGS AF: 0.232 AC: 809 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.51
PhyloP100		0.0050
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: rs9769826; hg19: chr7-155099656;