19-7184640-GGAGAGAGAGAGA-GGAGAGAGA

Variant names:

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

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.653-7_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

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-GGAGA-G is Benign according to our data. Variant chr19-7184640-GGAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 435512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7184640-GGAGA-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-7_653-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-7_653-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-7_653-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-7_653-4delTCTC		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.653-7_653-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-7_653-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-7_628-4delTCTC		splice_region_variant, intron_variant	Intron 2 of 9	1

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

GnomAD3 exomes AF: 0.00387 AC: 533 AN: 137742 Hom.: 1 AF XY: 0.00370 AC XY: 284 AN XY: 76688

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 SAS exome AF: 0.00324

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

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.00158

Gnomad4 SAS exome AF: 0.00340

Gnomad4 FIN exome AF: 0.00239

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00248

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

Gnomad4 AFR AF: 0.00357

Gnomad4 AMR AF: 0.000280

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000213

Gnomad4 NFE AF: 0.0000604

Gnomad4 OTH AF: 0.00154

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 v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3835070; hg19: chr19-7184651;