chr19-7184640-GGAGA-G

Variant names:

• chr19-7184640-GGAGA-G
• rs3835070
• NM_000208.4:c.653-7_653-4delTCTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000208.4(INSR):​c.653-7_653-4delTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,367,248 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.353
• 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 -16 ACMG points.

• BP6: Variant 19-7184640-GGAGA-G is Benign according to our data. Variant chr19-7184640-GGAGA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.001 (143/142346) while in subpopulation AFR AF = 0.00357 (130/36388). AF 95% confidence interval is 0.00307. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.653-7_653-4delTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-7_653-4delTCTC		splice_region 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.653-7_653-4delTCTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-7_653-4delTCTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-7_628-4delTCTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 144 AN: 142256 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000280

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000603

Gnomad OTH AF: 0.00156

GnomAD2 exomes AF: 0.00387 AC: 533 AN: 137742 AF XY: 0.00370

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.00502

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00270

Gnomad FIN exome AF: 0.00386

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00209 AC: 2564 AN: 1224902 Hom.: 2 AF XY: 0.00213 AC XY: 1305 AN XY: 613246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00266 AC: 66 AN: 24778

American (AMR) AF: 0.00425 AC: 166 AN: 39074

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 48 AN: 22814

East Asian (EAS) AF: 0.00158 AC: 57 AN: 36120

South Asian (SAS) AF: 0.00340 AC: 237 AN: 69784

European-Finnish (FIN) AF: 0.00239 AC: 111 AN: 46540

Middle Eastern (MID) AF: 0.00257 AC: 10 AN: 3892

European-Non Finnish (NFE) AF: 0.00187 AC: 1743 AN: 931096

Other (OTH) AF: 0.00248 AC: 126 AN: 50804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00100 AC: 143 AN: 142346 Hom.: 0 Cov.: 0 AF XY: 0.00106 AC XY: 73 AN XY: 69022

African (AFR) AF: 0.00357 AC: 130 AN: 36388

American (AMR) AF: 0.000280 AC: 4 AN: 14296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4986

South Asian (SAS) AF: 0.00 AC: 0 AN: 4496

European-Finnish (FIN) AF: 0.000213 AC: 2 AN: 9400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000604 AC: 4 AN: 66274

Other (OTH) AF: 0.00154 AC: 3 AN: 1944

Alfa AF: 0.00367 Hom.: 141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 15, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=84/16	polymorphism

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;