7-155298328-C-T

Position:

• chr7-155298328-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005542.6(INSIG1):​c.43C>T​(p.His15Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INSIG1 NM_005542.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.443

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]

INSIG1-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06937474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSIG1	NM_005542.6	c.43C>T	p.His15Tyr	missense_variant	2/6	ENST00000340368.9	NP_005533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSIG1	ENST00000340368.9	c.43C>T	p.His15Tyr	missense_variant	2/6	1	NM_005542.6	ENSP00000344741.4
INSIG1	ENST00000344756.8	c.43C>T	p.His15Tyr	missense_variant	2/6	5		ENSP00000340010.4
INSIG1	ENST00000342407.5	c.43C>T	p.His15Tyr	missense_variant	2/4	2		ENSP00000344035.5
INSIG1	ENST00000425172.1	c.43C>T	p.His15Tyr	missense_variant	2/2	2		ENSP00000414691.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000294 AC: 4 AN: 1358450 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 668560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000374

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000867 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2024

The c.43C>T (p.H15Y) alteration is located in exon 2 (coding exon 1) of the INSIG1 gene. This alteration results from a C to T substitution at nucleotide position 43, causing the histidine (H) at amino acid position 15 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.096	.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.86	N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.098	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.17	B;B;.;.
Vest4		0.19
MutPred		0.24		Loss of disorder (P = 0.0069);Loss of disorder (P = 0.0069);Loss of disorder (P = 0.0069);Loss of disorder (P = 0.0069);
MVP		0.26
MPC		1.0
ClinPred		0.062	T
GERP RS		-7.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.046
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs748711429; hg19: chr7-155090038;