Menu
GeneBe

7-155298521-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005542.6(INSIG1):c.236C>G(p.Thr79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000815 in 1,594,834 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

INSIG1
NM_005542.6 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.020313352).
BP6
Variant 7-155298521-C-G is Benign according to our data. Variant chr7-155298521-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3109900.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INSIG1NM_005542.6 linkuse as main transcriptc.236C>G p.Thr79Ser missense_variant 2/6 ENST00000340368.9
INSIG1-DTNR_183448.1 linkuse as main transcriptn.460G>C non_coding_transcript_exon_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INSIG1ENST00000340368.9 linkuse as main transcriptc.236C>G p.Thr79Ser missense_variant 2/61 NM_005542.6 P1O15503-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000276
AC:
6
AN:
217234
Hom.:
0
AF XY:
0.0000170
AC XY:
2
AN XY:
117982
show subpopulations
Gnomad AFR exome
AF:
0.000294
Gnomad AMR exome
AF:
0.0000631
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000347
AC:
5
AN:
1442618
Hom.:
0
Cov.:
31
AF XY:
0.00000419
AC XY:
3
AN XY:
716290
show subpopulations
Gnomad4 AFR exome
AF:
0.0000905
Gnomad4 AMR exome
AF:
0.0000473
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.000193
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 23, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.58
Cadd
Benign
10
Dann
Benign
0.20
DEOGEN2
Benign
0.070
T;.;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.30
T;T;T
M_CAP
Benign
0.0085
T
MetaRNN
Benign
0.020
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.9
N;.;N
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
0.49
N;N;N
REVEL
Benign
0.042
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.028
MutPred
0.17
Loss of glycosylation at T79 (P = 0.0213);Loss of glycosylation at T79 (P = 0.0213);Loss of glycosylation at T79 (P = 0.0213);
MVP
0.26
MPC
0.76
ClinPred
0.018
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.041
gMVP
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371087646; hg19: chr7-155090231; API