Variant 15-98649652-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000875.5(IGF1R):c.71C>G(p.Ser24Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,458,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.440

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:

IRAIN (HGNC:):

IRAIN links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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=0.22191292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.71C>G	p.Ser24Trp	missense_variant	1/21	ENST00000650285.1	NP_000866.1
IRAIN	NR_126453.2 linkuse as main transcript	n.1136G>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
IGF1R	ENST00000650285.1 linkuse as main transcript	c.71C>G	p.Ser24Trp	missense_variant	1/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000559925.5 linkuse as main transcript	n.71C>G		non_coding_transcript_exon_variant	1/10	1
IGF1R	ENST00000649865.1 linkuse as main transcript	c.71C>G	p.Ser24Trp	missense_variant	1/21			ENSP00000496919	A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246874

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1458442

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

725554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000602

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.71C>G (p.S24W) alteration is located in exon 1 (coding exon 1) of the IGF1R gene. This alteration results from a C to G substitution at nucleotide position 71, causing the serine (S) at amino acid position 24 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.54

D;.;D;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.82

.;.;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.0

N;.;N;.

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.73

.;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.070

.;.;T;T

Sift4G

Uncertain

0.023

.;.;D;D

Polyphen

0.29

B;P;B;P

Vest4

0.46, 0.41

MutPred

0.50

Gain of catalytic residue at S24 (P = 0.0576);Gain of catalytic residue at S24 (P = 0.0576);Gain of catalytic residue at S24 (P = 0.0576);Gain of catalytic residue at S24 (P = 0.0576);

MVP

0.74

MPC

1.2

ClinPred

0.22

GERP RS

1.7

Varity_R

0.10

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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