rs3842753

Variant names:

• chr11-2159830-T-G
• rs3842753
• NM_000207.3:c.*22A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-2159830-T-G
• chr11-2159830-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000207.3(INS):​c.*22A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,607,734 control chromosomes in the GnomAD database, including 415,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.61 (32006 hom., cov: 33)
  • Exomes 𝑓: 0.72 (383754 hom.)
• Consequence: INS NM_000207.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.05
• Publications: 55 publications found

Genes affected

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]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.279031E-7).
• BP6: Variant 11-2159830-T-G is Benign according to our data. Variant chr11-2159830-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304051.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

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.*22A>C		3_prime_UTR	Exon 3 of 3	NP_000198.1	P01308-1
	INS	NM_001185097.2		c.*22A>C		3_prime_UTR	Exon 3 of 3	NP_001172026.1	I3WAC9
	INS	NM_001185098.2		c.*22A>C		3_prime_UTR	Exon 2 of 2	NP_001172027.1	P01308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.*22A>C		3_prime_UTR	Exon 3 of 3	ENSP00000370731.5	P01308-1
	INS	ENST00000250971.7	TSL:1	c.*22A>C		3_prime_UTR	Exon 3 of 3	ENSP00000250971.3	P01308-1
	INS	ENST00000397262.5	TSL:1	c.*22A>C		3_prime_UTR	Exon 2 of 2	ENSP00000380432.1	P01308-1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92705 AN: 151854 Hom.: 31998 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.793

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.671

GnomAD2 exomes AF: 0.733 AC: 176653 AN: 240868 AF XY: 0.744

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.701

Gnomad EAS exome AF: 0.953

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.736

GnomAD4 exome AF: 0.720 AC: 1048832 AN: 1455762 Hom.: 383754 Cov.: 40 AF XY: 0.725 AC XY: 524628 AN XY: 723788

African (AFR) AF: 0.241 AC: 8062 AN: 33424

American (AMR) AF: 0.762 AC: 33643 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18321 AN: 25984

East Asian (EAS) AF: 0.958 AC: 37927 AN: 39572

South Asian (SAS) AF: 0.827 AC: 70474 AN: 85206

European-Finnish (FIN) AF: 0.793 AC: 41114 AN: 51822

Middle Eastern (MID) AF: 0.790 AC: 4552 AN: 5762

European-Non Finnish (NFE) AF: 0.713 AC: 791675 AN: 1109700

Other (OTH) AF: 0.716 AC: 43064 AN: 60138

GnomAD4 genome AF: 0.610 AC: 92730 AN: 151972 Hom.: 32006 Cov.: 33 AF XY: 0.623 AC XY: 46299 AN XY: 74286

African (AFR) AF: 0.260 AC: 10757 AN: 41380

American (AMR) AF: 0.725 AC: 11087 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2463 AN: 3470

East Asian (EAS) AF: 0.949 AC: 4890 AN: 5154

South Asian (SAS) AF: 0.831 AC: 4003 AN: 4816

European-Finnish (FIN) AF: 0.793 AC: 8395 AN: 10590

Middle Eastern (MID) AF: 0.798 AC: 233 AN: 292

European-Non Finnish (NFE) AF: 0.719 AC: 48874 AN: 67952

Other (OTH) AF: 0.675 AC: 1424 AN: 2110

Alfa AF: 0.661 Hom.: 16332

Bravo AF: 0.587

TwinsUK AF: 0.714 AC: 2648

ALSPAC AF: 0.697 AC: 2688

ESP6500AA AF: 0.269 AC: 1174

ESP6500EA AF: 0.690 AC: 5919

ExAC AF: 0.716 AC: 85906

Asia WGS AF: 0.842 AC: 2928 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Maturity-onset diabetes of the young type 10 (2)
-	-	2	not provided (2)
-	-	1	Autosomal recessive DOPA responsive dystonia (1)
-	1	-	Diabetes mellitus type 1 (1)
-	-	1	Diabetes mellitus, permanent neonatal 4 (1)
-	-	1	Hyperproinsulinemia (1)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)
-	-	1	Type 1 diabetes mellitus 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.70
DANN	Benign	0.45
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00072	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-0.89	T
PhyloP100		1.0
PROVEAN	Benign	0.19	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
ClinPred		0.0091	T
GERP RS		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3842753; hg19: chr11-2181060;