chr19-7184751-A-G

Variant names:

• chr19-7184751-A-G
• rs891088
• NM_000208.4:c.653-114T>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.653-114T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 777,212 control chromosomes in the GnomAD database, including 34,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8511 hom., cov: 32)
  • Exomes 𝑓: 0.27 (26393 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.725
• Publications: 52 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

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

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-7184751-A-G is Benign according to our data. Variant chr19-7184751-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286680.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.653-114T>C		intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-114T>C		intron	N/A	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.653-114T>C		intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-114T>C		intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-114T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48828 AN: 151888 Hom.: 8479 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.271 AC: 169620 AN: 625206 Hom.: 26393 AF XY: 0.273 AC XY: 86678 AN XY: 317048

African (AFR) AF: 0.471 AC: 7171 AN: 15228

American (AMR) AF: 0.296 AC: 3457 AN: 11688

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 2977 AN: 12428

East Asian (EAS) AF: 0.222 AC: 5329 AN: 23998

South Asian (SAS) AF: 0.463 AC: 10679 AN: 23074

European-Finnish (FIN) AF: 0.287 AC: 4955 AN: 17264

Middle Eastern (MID) AF: 0.290 AC: 589 AN: 2034

European-Non Finnish (NFE) AF: 0.257 AC: 126147 AN: 490866

Other (OTH) AF: 0.291 AC: 8316 AN: 28626

GnomAD4 genome AF: 0.322 AC: 48908 AN: 152006 Hom.: 8511 Cov.: 32 AF XY: 0.324 AC XY: 24075 AN XY: 74306

African (AFR) AF: 0.449 AC: 18619 AN: 41430

American (AMR) AF: 0.290 AC: 4422 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1046 AN: 5192

South Asian (SAS) AF: 0.399 AC: 1928 AN: 4828

European-Finnish (FIN) AF: 0.294 AC: 3102 AN: 10544

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17881 AN: 67976

Other (OTH) AF: 0.333 AC: 705 AN: 2114

Alfa AF: 0.281 Hom.: 29796

Bravo AF: 0.324

Asia WGS AF: 0.372 AC: 1289 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		0.72
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: rs891088; hg19: chr19-7184762;