19-7112861-A-G

Variant names:

• chr19-7112861-A-G
• rs1366601
• NM_000208.4:c.*4195T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000208.4(INSR):​c.*4195T>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 0.059 in 149,810 control chromosomes in the GnomAD database, including 724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.059 (724 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INSR NM_000208.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -3.09
• Publications: 2 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):

• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• insulin-resistance syndrome type A

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

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

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-7112861-A-G is Benign according to our data. Variant chr19-7112861-A-G is described in ClinVar as Benign. ClinVar VariationId is 330355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 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.*4195T>C		3_prime_UTR	Exon 22 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.*4195T>C		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.*4195T>C		3_prime_UTR	Exon 22 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.*4195T>C		3_prime_UTR	Exon 21 of 21	ENSP00000342838.4	P06213-2

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8810 AN: 149696 Hom.: 719 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.000391

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.00186

Gnomad OTH AF: 0.0503

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

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

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0590 AC: 8833 AN: 149810 Hom.: 724 Cov.: 31 AF XY: 0.0594 AC XY: 4344 AN XY: 73136

African (AFR) AF: 0.180 AC: 7369 AN: 40874

American (AMR) AF: 0.0292 AC: 438 AN: 14994

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 40 AN: 3440

East Asian (EAS) AF: 0.134 AC: 688 AN: 5120

South Asian (SAS) AF: 0.0131 AC: 62 AN: 4732

European-Finnish (FIN) AF: 0.000391 AC: 4 AN: 10234

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.00186 AC: 125 AN: 67158

Other (OTH) AF: 0.0498 AC: 103 AN: 2070

Alfa AF: 0.0258 Hom.: 124

Bravo AF: 0.0665

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	-0.91
CADD	Benign	0.16
DANN	Benign	0.13
PhyloP100		-3.1
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: rs1366601; hg19: chr19-7112872;