7-155298617-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005542.6(INSIG1):c.332T>C(p.Val111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,520 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 1 hom. )
Consequence
INSIG1
NM_005542.6 missense
NM_005542.6 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 7.62
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]
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ACMG classification
Classification made for transcript
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=0.11482385).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INSIG1 | NM_005542.6 | c.332T>C | p.Val111Ala | missense_variant | 2/6 | ENST00000340368.9 | |
INSIG1-DT | NR_183448.1 | n.364A>G | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INSIG1 | ENST00000340368.9 | c.332T>C | p.Val111Ala | missense_variant | 2/6 | 1 | NM_005542.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000342 AC: 52AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000234 AC: 58AN: 247548Hom.: 0 AF XY: 0.000208 AC XY: 28AN XY: 134314
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GnomAD4 exome AF: 0.000151 AC: 220AN: 1461254Hom.: 1 Cov.: 31 AF XY: 0.000150 AC XY: 109AN XY: 726910
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GnomAD4 genome ? AF: 0.000342 AC: 52AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | The c.332T>C (p.V111A) alteration is located in exon 2 (coding exon 1) of the INSIG1 gene. This alteration results from a T to C substitution at nucleotide position 332, causing the valine (V) at amino acid position 111 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at