rs2229764

chr15-98891587-C-Achr15-98891587-C-Gchr15-98891587-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000875.5(IGF1R):c.903C>A(p.Gly301=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,604,766 control chromosomes in the GnomAD database, including 555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (38 hom., cov: 32)
  • Exomes 𝑓: 0.023 (517 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.536

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 15-98891587-C-A is Benign according to our data. Variant chr15-98891587-C-A is described in ClinVar as [Benign]. Clinvar id is 317444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98891587-C-A is described in Lovd as [Benign]. Variant chr15-98891587-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.536 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0168 (2565/152310) while in subpopulation SAS AF= 0.0396 (191/4820). AF 95% confidence interval is 0.035. There are 38 homozygotes in gnomad4. There are 1226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.903C>A	p.Gly301=	synonymous_variant	3/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.903C>A	p.Gly301=	synonymous_variant	3/21		NM_000875.5	P4
	ENST00000558736.1	n.69+1880G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2564 AN: 152192 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0229 AC: 5579 AN: 243976 Hom.: 131 AF XY: 0.0253 AC XY: 3348 AN XY: 132494

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0484

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0227 AC: 32965 AN: 1452456 Hom.: 517 Cov.: 33 AF XY: 0.0239 AC XY: 17295 AN XY: 722868

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0502

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0480

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.0220

Gnomad4 OTH exome AF: 0.0235

GnomAD4 genome AF: 0.0168 AC: 2565 AN: 152310 Hom.: 38 Cov.: 32 AF XY: 0.0165 AC XY: 1226 AN XY: 74476

Gnomad4 AFR AF: 0.00404

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0573

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0154 Hom.: 9

Bravo AF: 0.0153

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0271

EpiControl AF: 0.0258

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Growth delay due to insulin-like growth factor I resistance 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

Invitae

Jan 29, 2024

- -

IGF1R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	8.1
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs2229764; hg19: chr15-99434816; COSMIC: COSV51279783;