rs45451896

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000875.5(IGF1R):c.1976G>A(p.Arg659Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,614,138 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 4 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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=0.008165836).

BP6

Variant 15-98916111-G-A is Benign according to our data. Variant chr15-98916111-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 884758.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000289 (44/152290) while in subpopulation SAS AF= 0.00145 (7/4828). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.1976G>A	p.Arg659Gln	missense_variant	9/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
IGF1R	ENST00000650285.1 linkuse as main transcript	c.1976G>A	p.Arg659Gln	missense_variant	9/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000559925.5 linkuse as main transcript	n.1976G>A		non_coding_transcript_exon_variant	9/10	1
IGF1R	ENST00000649865.1 linkuse as main transcript	c.1976G>A	p.Arg659Gln	missense_variant	9/21			ENSP00000496919	A1
IGF1R	ENST00000560144.1 linkuse as main transcript	c.207G>A	p.Pro69=	synonymous_variant, NMD_transcript_variant	2/4	3		ENSP00000456950

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000660

AC:

166

AN:

251448

Hom.:

AF XY:

0.000773

AC XY:

105

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00219

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000326

AC:

476

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

285

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000191

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000289

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000476

Hom.:

Bravo

AF:

0.000325

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000708

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance

Uncertain:1

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.36

T;.;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.87

.;.;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.0082

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.63

N;.;N;.

MutationTaster

Benign

0.91

D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

0.92

.;.;N;N

REVEL

Benign

0.078

Sift

Benign

1.0

.;.;T;T

Sift4G

Benign

0.95

.;.;T;T

Polyphen

0.0020

B;B;B;B

Vest4

0.23, 0.20

MVP

0.46

MPC

0.71

ClinPred

0.024

GERP RS

0.57

Varity_R

0.061

gMVP

0.34

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