INSIG1 p.Thr79Ser

Variant names:

• chr7-155298520-A-T
• NM_005542.6:c.235A>T
• INSIG1 p.Thr79Ser

Your query was ambiguous. Multiple possible variants found:

• chr7-155298520-A-T
• chr7-155298521-C-G
• chr7-155298520-ACC-TCT
• chr7-155298520-ACC-TCA
• chr7-155298520-ACC-TCG
• chr7-155298521-CC-GT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005542.6(INSIG1):​c.235A>T​(p.Thr79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INSIG1 NM_005542.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• Publications: 0 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]

INSIG1-DT (HGNC:55155): (INSIG1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066447645).

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.235A>T	p.Thr79Ser	missense	Exon 2 of 6	NP_005533.2
	INSIG1	NM_001346590.2		c.235A>T	p.Thr79Ser	missense	Exon 2 of 7	NP_001333519.1	A4D2M9
	INSIG1	NM_001346591.2		c.235A>T	p.Thr79Ser	missense	Exon 2 of 7	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.235A>T	p.Thr79Ser	missense	Exon 2 of 6	ENSP00000344741.4	O15503-1
	INSIG1	ENST00000885536.1		c.235A>T	p.Thr79Ser	missense	Exon 2 of 6	ENSP00000555595.1
	INSIG1	ENST00000885537.1		c.235A>T	p.Thr79Ser	missense	Exon 2 of 6	ENSP00000555596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.19
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N
PhyloP100		3.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.22
Mutation Taster		=91/9	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-155090230;