Genetic Variant IGF1R:p.Arg40Leu (chr15-98707586-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000875.5(IGF1R):c.119G>T(p.Arg40Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as protective (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

protective no assertion criteria provided B:1

Conservation

PhyloP100: 9.86

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-98707585-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 635840.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5 link	c.119G>T	p.Arg40Leu	missense_variant	Exon 2 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IGF1R	ENST00000650285.1 link	c.119G>T	p.Arg40Leu	missense_variant	Exon 2 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5 link	n.119G>T		non_coding_transcript_exon_variant	Exon 2 of 10	1
IGF1R	ENST00000649865.1 link	c.119G>T	p.Arg40Leu	missense_variant	Exon 2 of 21			ENSP00000496919.1
IGF1R	ENST00000558355.1 link	c.-245G>T		upstream_gene_variant		2		ENSP00000453630.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance

Benign:1

Dec 12, 2017

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;.;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

3.4

M;.;M;.

PhyloP100

9.9

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.0

.;.;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

.;.;D;D

Vest4

0.0

ClinPred

0.99

GERP RS

5.5

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.77

gMVP

0.91

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over