rs13306451

Positions:

• chr19-7142813-T-C
• chr19-7142813-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000208.4(INSR):​c.2542+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,613,910 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (50 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (114 hom.)
• Consequence: INSR NM_000208.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.08482
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.07

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-7142813-T-C is Benign according to our data. Variant chr19-7142813-T-C is described in ClinVar as [Benign]. Clinvar id is 330457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7142813-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0184 (2807/152298) while in subpopulation AFR AF= 0.0437 (1817/41562). AF 95% confidence interval is 0.042. There are 50 homozygotes in gnomad4. There are 1370 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.2542+3A>G		splice_donor_region_variant, intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.2506+3A>G		splice_donor_region_variant, intron_variant
INSR	XM_011527988.3	c.2542+3A>G		splice_donor_region_variant, intron_variant
INSR	XM_011527989.4	c.2506+3A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.2542+3A>G		splice_donor_region_variant, intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.2506+3A>G		splice_donor_region_variant, intron_variant		1		P3
INSR	ENST00000597211.1	n.225+3A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2791 AN: 152180 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0113 AC: 2815 AN: 249188 Hom.: 42 AF XY: 0.0100 AC XY: 1355 AN XY: 135094

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0393

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00964

GnomAD4 exome AF: 0.00834 AC: 12190 AN: 1461612 Hom.: 114 Cov.: 32 AF XY: 0.00794 AC XY: 5772 AN XY: 727112

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00639

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.0184 AC: 2807 AN: 152298 Hom.: 50 Cov.: 31 AF XY: 0.0184 AC XY: 1370 AN XY: 74484

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0414

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0121 Hom.: 13

Bravo AF: 0.0200

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00510

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.085
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.020		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: rs13306451; hg19: chr19-7142824; COSMIC: COSV57164958;