chr19-7166530-A-G

Variant names:

• chr19-7166530-A-G
• rs3815901
• NM_000208.4:c.1611-126T>C

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.1611-126T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,020,650 control chromosomes in the GnomAD database, including 108,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19646 hom., cov: 32)
  • Exomes 𝑓: 0.44 (88474 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.403
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-7166530-A-G is Benign according to our data. Variant chr19-7166530-A-G is described in ClinVar as Benign. ClinVar VariationId is 1231520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.639 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.1611-126T>C		intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.1611-126T>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.1611-126T>C		intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.1611-126T>C		intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.1586-126T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75831 AN: 151884 Hom.: 19601 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.530

GnomAD4 exome AF: 0.443 AC: 385118 AN: 868648 Hom.: 88474 AF XY: 0.447 AC XY: 199564 AN XY: 446248

African (AFR) AF: 0.644 AC: 13562 AN: 21066

American (AMR) AF: 0.400 AC: 13102 AN: 32782

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 11660 AN: 21402

East Asian (EAS) AF: 0.287 AC: 9544 AN: 33286

South Asian (SAS) AF: 0.543 AC: 36366 AN: 67026

European-Finnish (FIN) AF: 0.448 AC: 15720 AN: 35068

Middle Eastern (MID) AF: 0.536 AC: 1944 AN: 3626

European-Non Finnish (NFE) AF: 0.431 AC: 264338 AN: 613764

Other (OTH) AF: 0.465 AC: 18882 AN: 40628

GnomAD4 genome AF: 0.499 AC: 75920 AN: 152002 Hom.: 19646 Cov.: 32 AF XY: 0.499 AC XY: 37106 AN XY: 74298

African (AFR) AF: 0.645 AC: 26764 AN: 41466

American (AMR) AF: 0.428 AC: 6520 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1862 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1669 AN: 5172

South Asian (SAS) AF: 0.550 AC: 2651 AN: 4816

European-Finnish (FIN) AF: 0.466 AC: 4921 AN: 10568

Middle Eastern (MID) AF: 0.517 AC: 151 AN: 292

European-Non Finnish (NFE) AF: 0.437 AC: 29709 AN: 67950

Other (OTH) AF: 0.535 AC: 1130 AN: 2114

Alfa AF: 0.498 Hom.: 2988

Bravo AF: 0.501

Asia WGS AF: 0.518 AC: 1803 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.79
DANN	Benign	0.37
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3815901; hg19: chr19-7166541; COSMIC: COSV57172887;