rs34516635

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000875.5(IGF1R):c.1310G>A(p.Arg437His) variant causes a missense change. The variant allele was found at a frequency of 0.00355 in 1,614,058 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 16 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.98

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, IGF1R

BP4

Computational evidence support a benign effect (MetaRNN=0.008615285).

BP6

Variant 15-98908747-G-A is Benign according to our data. Variant chr15-98908747-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98908747-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00279 (425/152254) while in subpopulation NFE AF= 0.00448 (305/68030). AF 95% confidence interval is 0.00407. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	6/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	6/21		NM_000875.5	P4

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

425

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00448

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00314

AC:

790

AN:

251266

Hom.:

AF XY:

0.00322

AC XY:

438

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.000984

Gnomad ASJ exome

AF:

0.00724

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00248

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00461

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00363

AC:

5311

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2697

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00861

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00261

Gnomad4 FIN exome

AF:

0.00249

Gnomad4 NFE exome

AF:

0.00401

Gnomad4 OTH exome

AF:

0.00303

GnomAD4 genome

AF:

0.00279

AC:

425

AN:

152254

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00448

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00420

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00321

AC:

390

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	IGF1R: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 01, 2014

- -

Growth delay due to insulin-like growth factor I resistance

Benign:1

Likely benign, 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). 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

IGF1R-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Benign

0.27

DEOGEN2

Uncertain

0.52

D;.;D;.;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.68

M_CAP

Benign

0.034

MetaRNN

Benign

0.0086

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.84

N;.;N;.;.

MutationTaster

Benign

0.95

D;D

PrimateAI

Benign

0.28

Polyphen

0.0

B;B;B;B;.

Vest4

0.10, 0.11

MVP

0.54

MPC

0.77

ClinPred

0.0041

GERP RS

2.5

Varity_R

0.046

gMVP

0.62

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