rs2229764

Variant names:

• chr15-98891587-C-A
• rs2229764
• NM_000875.5:c.903C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-98891587-C-A
• chr15-98891587-C-G
• chr15-98891587-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000875.5(IGF1R):​c.903C>A​(p.Gly301Gly) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G301G) has been classified as Uncertain significance.

• 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:6
• Conservation: PhyloP100: -0.536
• Publications: 6 publications found

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]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000259621 (HGNC:58474):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 317444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.903C>A	p.Gly301Gly	synonymous_variant	Exon 3 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.903C>A	p.Gly301Gly	synonymous_variant	Exon 3 of 21		NM_000875.5	ENSP00000497069.1

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

GnomAD2 exomes AF: 0.0229 AC: 5579 AN: 243976 AF XY: 0.0253

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 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

African (AFR) AF: 0.00296 AC: 99 AN: 33474

American (AMR) AF: 0.0110 AC: 492 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0502 AC: 1311 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0480 AC: 4138 AN: 86244

European-Finnish (FIN) AF: 0.0189 AC: 837 AN: 44174

Middle Eastern (MID) AF: 0.0383 AC: 221 AN: 5768

European-Non Finnish (NFE) AF: 0.0220 AC: 24444 AN: 1111930

Other (OTH) AF: 0.0235 AC: 1420 AN: 60328

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

African (AFR) AF: 0.00404 AC: 168 AN: 41586

American (AMR) AF: 0.0108 AC: 166 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0396 AC: 191 AN: 4820

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1562 AN: 68014

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0206 Hom.: 50

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Growth delay due to insulin-like growth factor I resistance Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

IGF1R-related disorder Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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