19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr19-7184640-G-GGAGAGAGAGAGAGAGAGAGA
• rs3835070
• NM_000208.4:c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000208.4(INSR):​c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 0)
  • Exomes 𝑓: 0.00019 (5 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-7184640-G-GGAGAGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGAGAGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 728898.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 = 0.00467 (663/141952) while in subpopulation AFR AF= 0.0168 (603/35984). AF 95% confidence interval is 0.0157. There are 8 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.653-4_653-3insTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-4_653-3insTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-4_628-3insTCTCTCTCTCTCTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 664 AN: 141858 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.000881

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000166

Gnomad OTH AF: 0.00467

GnomAD4 exome AF: 0.000192 AC: 237 AN: 1233760 Hom.: 5 Cov.: 17 AF XY: 0.000154 AC XY: 95 AN XY: 617868

Gnomad4 AFR exome AF: 0.00551

Gnomad4 AMR exome AF: 0.000632

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000426

Gnomad4 FIN exome AF: 0.000127

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.000782

GnomAD4 genome AF: 0.00467 AC: 663 AN: 141952 Hom.: 8 Cov.: 0 AF XY: 0.00473 AC XY: 326 AN XY: 68860

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.00245

Gnomad4 ASJ AF: 0.000881

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000106

Gnomad4 NFE AF: 0.000166

Gnomad4 OTH AF: 0.00463

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

May 14, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Dec 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3835070; hg19: chr19-7184651;