rs1051690

Variant names:

• chr19-7116952-T-C
• rs1051690
• NM_000208.4:c.*104A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-7116952-T-C
• chr19-7116952-T-A
• chr19-7116952-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.*104A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 920,464 control chromosomes in the GnomAD database, including 331,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53240 hom., cov: 29)
  • Exomes 𝑓: 0.85 (278091 hom.)
• Consequence: INSR NM_000208.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.550
• Publications: 50 publications found

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-7116952-T-C is Benign according to our data. Variant chr19-7116952-T-C is described in ClinVar as Benign. ClinVar VariationId is 330436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. 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
	INSR	NM_000208.4	MANE Select	c.*104A>G		3_prime_UTR	Exon 22 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.*104A>G		3_prime_UTR	Exon 21 of 21	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.*104A>G		3_prime_UTR	Exon 22 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.*104A>G		3_prime_UTR	Exon 21 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.*104A>G		3_prime_UTR	Exon 22 of 22	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.837 AC: 127054 AN: 151830 Hom.: 53192 Cov.: 29

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.855

GnomAD4 exome AF: 0.849 AC: 652733 AN: 768516 Hom.: 278091 Cov.: 10 AF XY: 0.852 AC XY: 348143 AN XY: 408440

African (AFR) AF: 0.821 AC: 16527 AN: 20140

American (AMR) AF: 0.925 AC: 40009 AN: 43242

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 19147 AN: 21522

East Asian (EAS) AF: 0.955 AC: 34987 AN: 36638

South Asian (SAS) AF: 0.910 AC: 65249 AN: 71714

European-Finnish (FIN) AF: 0.774 AC: 40427 AN: 52234

Middle Eastern (MID) AF: 0.890 AC: 3714 AN: 4172

European-Non Finnish (NFE) AF: 0.833 AC: 400693 AN: 481228

Other (OTH) AF: 0.850 AC: 31980 AN: 37626

GnomAD4 genome AF: 0.837 AC: 127159 AN: 151948 Hom.: 53240 Cov.: 29 AF XY: 0.838 AC XY: 62203 AN XY: 74244

African (AFR) AF: 0.817 AC: 33867 AN: 41448

American (AMR) AF: 0.892 AC: 13608 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 3082 AN: 3470

East Asian (EAS) AF: 0.954 AC: 4922 AN: 5158

South Asian (SAS) AF: 0.914 AC: 4392 AN: 4806

European-Finnish (FIN) AF: 0.772 AC: 8127 AN: 10532

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56344 AN: 67968

Other (OTH) AF: 0.858 AC: 1808 AN: 2108

Alfa AF: 0.839 Hom.: 108045

Bravo AF: 0.845

Asia WGS AF: 0.935 AC: 3250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	-	1	Leprechaunism syndrome (1)
-	-	1	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.32
PhyloP100		0.55
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: rs1051690; hg19: chr19-7116963; COSMIC: COSV105137620; COSMIC: COSV105137620;