rs117440569

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000875.5(IGF1R):c.1336A>G(p.Met446Val) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,614,194 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M446I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 5.36

Publications

8 publications found

Variant links:

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

IGF1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011108369).

BP6

Variant 15-98908773-A-G is Benign according to our data. Variant chr15-98908773-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282332.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00147 (224/152350) while in subpopulation AMR AF = 0.00314 (48/15304). AF 95% confidence interval is 0.00243. There are 3 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.1336A>G	p.Met446Val	missense	Exon 6 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.1336A>G	p.Met446Val	missense	Exon 6 of 21	NP_001278787.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IGF1R	ENST00000650285.1	MANE Select	c.1336A>G	p.Met446Val	missense	Exon 6 of 21	ENSP00000497069.1
IGF1R	ENST00000559925.5	TSL:1	n.1336A>G		non_coding_transcript_exon	Exon 6 of 10
IGF1R	ENST00000649865.1		c.1336A>G	p.Met446Val	missense	Exon 6 of 21	ENSP00000496919.1

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

224

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00105

AC:

264

AN:

251244

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00171

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00137

AC:

2000

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

945

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00119

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000707

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00156

AC:

1730

AN:

1111982

Other (OTH)

AF:

0.00156

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00147

AC:

224

AN:

152350

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41582

American (AMR)

AF:

0.00314

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00194

AC:

132

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00117

AC:

142

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IGF1R: BS2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Aug 14, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 05, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: IGF1R c.1336A>G (p.Met446Val) results in a conservative amino acid change located in the Receptor L-domain (IPR000494) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251244 control chromosomes in the gnomAD database, including 1 homozygotes. c.1336A>G has been reported in the literature in one individual affected with Nodular melanoma, without strong evidence for causality (Stark_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Growth Delay Due To Insulin-Like Growth Factor I Resistance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37766469). ClinVar contains an entry for this variant (Variation ID: 282332). Based on the evidence outlined above, the variant was classified as likely benign.

Growth delay due to insulin-like growth factor I resistance

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

IGF1R-related disorder

Benign:1

Mar 02, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.082

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

M_CAP

Benign

0.017

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.38

PhyloP100

5.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Benign

0.17

Sift4G

Benign

0.38

Polyphen

0.0050

Vest4

0.53

MVP

0.78

MPC

0.64

ClinPred

0.022

GERP RS

5.8

Varity_R

0.25

gMVP

0.53

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over