rs2229765

Variant names:

• chr15-98934996-G-A
• rs2229765
• NM_000875.5:c.3129G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-98934996-G-A
• chr15-98934996-G-C
• chr15-98934996-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000875.5(IGF1R):​c.3129G>A​(p.Glu1043Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,534 control chromosomes in the GnomAD database, including 151,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11963 hom., cov: 31)
  • Exomes 𝑓: 0.43 (139575 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.148
• Publications: 107 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-98934996-G-A is Benign according to our data. Variant chr15-98934996-G-A is described in ClinVar as Benign. ClinVar VariationId is 194610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.148 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3129G>A	p.Glu1043Glu	synonymous_variant	Exon 16 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3129G>A	p.Glu1043Glu	synonymous_variant	Exon 16 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000560972.1	n.260-320G>A		intron_variant	Intron 3 of 3	1
IGF1R	ENST00000649865.1	c.3126G>A	p.Glu1042Glu	synonymous_variant	Exon 16 of 21			ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59377 AN: 151908 Hom.: 11959 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.397 AC: 99711 AN: 251348 AF XY: 0.398

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.433 AC: 632746 AN: 1461508 Hom.: 139575 Cov.: 46 AF XY: 0.430 AC XY: 312426 AN XY: 727054

African (AFR) AF: 0.295 AC: 9868 AN: 33476

American (AMR) AF: 0.343 AC: 15336 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 12358 AN: 26132

East Asian (EAS) AF: 0.311 AC: 12351 AN: 39696

South Asian (SAS) AF: 0.308 AC: 26585 AN: 86252

European-Finnish (FIN) AF: 0.422 AC: 22523 AN: 53412

Middle Eastern (MID) AF: 0.362 AC: 2088 AN: 5764

European-Non Finnish (NFE) AF: 0.456 AC: 506779 AN: 1111668

Other (OTH) AF: 0.412 AC: 24858 AN: 60390

GnomAD4 genome AF: 0.391 AC: 59409 AN: 152026 Hom.: 11963 Cov.: 31 AF XY: 0.388 AC XY: 28824 AN XY: 74304

African (AFR) AF: 0.299 AC: 12375 AN: 41454

American (AMR) AF: 0.379 AC: 5790 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1611 AN: 3468

East Asian (EAS) AF: 0.338 AC: 1741 AN: 5156

South Asian (SAS) AF: 0.316 AC: 1517 AN: 4806

European-Finnish (FIN) AF: 0.413 AC: 4365 AN: 10566

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30730 AN: 67976

Other (OTH) AF: 0.379 AC: 799 AN: 2108

Alfa AF: 0.423 Hom.: 33963

Bravo AF: 0.385

Asia WGS AF: 0.322 AC: 1120 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.438

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.15
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: rs2229765; hg19: chr15-99478225; COSMIC: COSV51291816;