NM_000208.4:c.653-5_653-4delTC

Variant names:

• chr19-7184640-GGA-G
• rs3835070
• NM_000208.4:c.653-5_653-4delTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.653-5_653-4delTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,315,650 control chromosomes in the GnomAD database, including 7,668 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1551 hom., cov: 0)
  • Exomes 𝑓: 0.13 (6117 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.176
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 19-7184640-GGA-G is Benign according to our data. Variant chr19-7184640-GGA-G is described in ClinVar as Benign. ClinVar VariationId is 196236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 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.653-5_653-4delTC		splice_region intron	N/A	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.653-5_653-4delTC		splice_region intron	N/A	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.653-5_653-4delTC		splice_region intron	N/A	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.653-5_653-4delTC		splice_region intron	N/A	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.628-5_628-4delTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.137 AC: 19520 AN: 142016 Hom.: 1550 Cov.: 0

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.144

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.238 AC: 32849 AN: 137742 AF XY: 0.243

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.129 AC: 151247 AN: 1173544 Hom.: 6117 AF XY: 0.133 AC XY: 77709 AN XY: 584838

African (AFR) AF: 0.0445 AC: 1078 AN: 24244

American (AMR) AF: 0.185 AC: 6948 AN: 37576

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 3872 AN: 20918

East Asian (EAS) AF: 0.157 AC: 5086 AN: 32302

South Asian (SAS) AF: 0.141 AC: 9544 AN: 67550

European-Finnish (FIN) AF: 0.195 AC: 8496 AN: 43506

Middle Eastern (MID) AF: 0.132 AC: 484 AN: 3654

European-Non Finnish (NFE) AF: 0.122 AC: 109201 AN: 895582

Other (OTH) AF: 0.136 AC: 6538 AN: 48212

GnomAD4 genome AF: 0.137 AC: 19523 AN: 142106 Hom.: 1551 Cov.: 0 AF XY: 0.141 AC XY: 9736 AN XY: 68910

African (AFR) AF: 0.0558 AC: 2027 AN: 36352

American (AMR) AF: 0.182 AC: 2597 AN: 14270

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 657 AN: 3400

East Asian (EAS) AF: 0.121 AC: 604 AN: 4978

South Asian (SAS) AF: 0.198 AC: 890 AN: 4486

European-Finnish (FIN) AF: 0.209 AC: 1954 AN: 9366

Middle Eastern (MID) AF: 0.137 AC: 39 AN: 284

European-Non Finnish (NFE) AF: 0.157 AC: 10361 AN: 66156

Other (OTH) AF: 0.164 AC: 317 AN: 1938

Alfa AF: 0.121 Hom.: 141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=97/3	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: rs3835070; hg19: chr19-7184651; COSMIC: COSV57161591;