Variant rs61740868 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_000875.5(IGF1R):c.3736C>G(p.Arg1246Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1246C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.35

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:55421): (SYNM antisense RNA 1)

SYNM-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain Protein kinase (size 275) in uniprot entity IGF1R_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000875.5

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.3736C>G	p.Arg1246Gly	missense_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IGF1R	ENST00000650285.1 linkuse as main transcript	c.3736C>G	p.Arg1246Gly	missense_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1 linkuse as main transcript	n.349-2686G>C		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1 linkuse as main transcript	c.3733C>G	p.Arg1245Gly	missense_variant	21/21			A1
IGF1R	ENST00000558751.1 linkuse as main transcript	n.330C>G		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251460

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;D;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

.;.;T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.3

L;.;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.0

.;.;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

.;.;D;D

Sift4G

Uncertain

0.034

.;.;D;D

Polyphen

0.94

P;D;P;D

Vest4

0.36, 0.35

MutPred

0.70

Loss of MoRF binding (P = 0.0528);.;Loss of MoRF binding (P = 0.0528);.;

MVP

0.90

MPC

0.069

ClinPred

0.97

GERP RS

4.4

Varity_R

0.87

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over