rs3745551

Variant names:

• chr19-7114277-C-T
• rs3745551
• NM_000208.4:c.*2779G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7114277-C-T
• chr19-7114277-C-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.*2779G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 152,046 control chromosomes in the GnomAD database, including 34,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (34930 hom., cov: 31)
  • Exomes 𝑓: 0.60 (10 hom.)
• Consequence: INSR NM_000208.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.48
• Publications: 17 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=-0.87).
• BP6: Variant 19-7114277-C-T is Benign according to our data. Variant chr19-7114277-C-T is described in ClinVar as Benign. ClinVar VariationId is 330380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 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.*2779G>A		3_prime_UTR	Exon 22 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.*2779G>A		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.*2779G>A		3_prime_UTR	Exon 22 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.*2779G>A		3_prime_UTR	Exon 21 of 21	ENSP00000342838.4	P06213-2

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102474 AN: 151876 Hom.: 34867 Cov.: 31

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.644

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.674

GnomAD4 exome AF: 0.596 AC: 31 AN: 52 Hom.: 10 Cov.: 0 AF XY: 0.595 AC XY: 25 AN XY: 42

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.587 AC: 27 AN: 46

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.675 AC: 102600 AN: 151994 Hom.: 34930 Cov.: 31 AF XY: 0.678 AC XY: 50336 AN XY: 74290

African (AFR) AF: 0.734 AC: 30436 AN: 41452

American (AMR) AF: 0.739 AC: 11293 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2278 AN: 3472

East Asian (EAS) AF: 0.788 AC: 4073 AN: 5170

South Asian (SAS) AF: 0.673 AC: 3242 AN: 4820

European-Finnish (FIN) AF: 0.621 AC: 6549 AN: 10548

Middle Eastern (MID) AF: 0.655 AC: 190 AN: 290

European-Non Finnish (NFE) AF: 0.627 AC: 42622 AN: 67956

Other (OTH) AF: 0.676 AC: 1419 AN: 2100

Alfa AF: 0.648 Hom.: 41585

Bravo AF: 0.684

Asia WGS AF: 0.747 AC: 2598 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.14
DANN	Benign	0.47
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3745551; hg19: chr19-7114288;