rs141802822

Positions:

chr15-98957347-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_000875.5(IGF1R):c.4009C>T(p.Arg1337Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,612,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.69

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:

SYNM-AS1 (HGNC:):

SYNM-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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=0.14948577).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000669 (102/152362) while in subpopulation AMR AF= 0.00111 (17/15310). AF 95% confidence interval is 0.000831. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.4009C>T	p.Arg1337Cys	missense_variant	21/21	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IGF1R	ENST00000650285.1 linkuse as main transcript	c.4009C>T	p.Arg1337Cys	missense_variant	21/21		NM_000875.5	ENSP00000497069.1	P08069
IGF1R	ENST00000649865.1 linkuse as main transcript	c.4006C>T	p.Arg1336Cys	missense_variant	21/21			ENSP00000496919.1	C9J5X1
SYNM-AS1	ENST00000559468.1 linkuse as main transcript	n.349-2959G>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000332

AC:

AN:

249916

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.000932

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000399

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000373

AC:

545

AN:

1459658

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

263

AN XY:

725774

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000403

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000669

AC:

102

AN:

152362

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000465

Hom.:

Bravo

AF:

0.000820

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25040157, 32939436, 35082626) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;D;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.071

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

0.083

MutationAssessor

Benign

1.9

L;.;L;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

.;.;D;D

REVEL

Uncertain

0.51

Sift

Benign

0.036

.;.;D;D

Sift4G

Uncertain

0.052

.;.;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.18, 0.17

MVP

0.87

MPC

0.075

ClinPred

0.031

GERP RS

3.6

Varity_R

0.20

gMVP

0.64

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