NM_000207.3:c.-115G>A

Variant names:

• chr11-2161265-C-T
• rs3842738
• ENST00000729705.1:n.174+2351C>T

Variant summary

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

The NM_000207.3(INS):​c.-115G>A variant causes a upstream gene 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INS NM_000207.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.61
• Publications: 10 publications found

Genes affected

ENSG00000295384 (HGNC:):

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

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 (BayesDel_noAF=-0.89).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. 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
	INS	NM_000207.3	MANE Select	c.-115G>A		upstream_gene	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.-115G>A		upstream_gene	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.-141G>A		upstream_gene	N/A	NP_001172026.1	I3WAC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000295384	ENST00000729705.1		n.174+2351C>T		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.225+2351C>T		intron	N/A
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-115G>A		upstream_gene	N/A	ENSP00000370731.5	P01308-1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000410 AC: 1 AN: 244156 Hom.: 0 Cov.: 3 AF XY: 0.00000803 AC XY: 1 AN XY: 124482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8486

American (AMR) AF: 0.00 AC: 0 AN: 10206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8680

East Asian (EAS) AF: 0.0000505 AC: 1 AN: 19806

South Asian (SAS) AF: 0.00 AC: 0 AN: 14414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1176

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 151118

Other (OTH) AF: 0.00 AC: 0 AN: 15248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 7943

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.90
PhyloP100		-1.6
PromoterAI		-0.0046	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3842738; hg19: chr11-2182495;