rs33958176

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_000875.5(IGF1R):c.1532G>A(p.Arg511Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,614,162 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 10 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 5.00

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 links:

IGF1R (HGNC:):

IGF1R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ 4.6449 (greater than threshold 3.09). GenCC has associacion of gene with growth delay due to insulin-like growth factor I resistance.

BP4

Computational evidence support a benign effect (MetaRNN=0.008615732).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (260/152276) while in subpopulation NFE AF= 0.00304 (207/68024). AF 95% confidence interval is 0.0027. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.1532G>A	p.Arg511Gln	missense_variant	7/21	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1 linkuse as main transcript	c.1532G>A	p.Arg511Gln	missense_variant	7/21		NM_000875.5	ENSP00000497069.1		P08069

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00304

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00159

AC:

400

AN:

251478

Hom.:

AF XY:

0.00163

AC XY:

222

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00296

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00278

AC:

4062

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1931

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00283

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00338

Gnomad4 OTH exome

AF:

0.00273

GnomAD4 genome

AF:

0.00171

AC:

260

AN:

152276

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00304

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00283

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.00311

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	IGF1R: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 17264177, 20625407, 22972910, 23771920) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2016	- -

Growth delay due to insulin-like growth factor I resistance

Uncertain:2Benign:1

protective, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 11, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2021

- -

IGF1R-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

.;.;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.0086

T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.1

M;.;M;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.57

.;.;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.60

.;.;T;T;T

Sift4G

Benign

0.57

.;.;T;T;T

Polyphen

0.19

B;P;B;P;.

Vest4

0.35, 0.38

MVP

0.85

MPC

0.73

ClinPred

0.021

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over