rs45493995

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000875.5(IGF1R):c.2894G>A(p.Ser965Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S965S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.79

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01000458).

BP6

Variant 15-98930243-G-A is Benign according to our data. Variant chr15-98930243-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 731844.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000394 (6/152364) while in subpopulation EAS AF = 0.00116 (6/5188). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5 link	c.2894G>A	p.Ser965Asn	missense_variant	Exon 15 of 21	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGF1R	ENST00000650285.1 link	c.2894G>A	p.Ser965Asn	missense_variant	Exon 15 of 21		NM_000875.5	ENSP00000497069.1	P08069
IGF1R	ENST00000560972.1 link	n.197G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1
IGF1R	ENST00000649865.1 link	c.2891G>A	p.Ser964Asn	missense_variant	Exon 15 of 21			ENSP00000496919.1	C9J5X1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000124

AC:

AN:

250604

AF XY:

0.0000591

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460518

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.000630

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111004

Other (OTH)

AF:

0.0000331

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: IGF1R c.2894G>A (p.Ser965Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250604 control chromosomes (gnomAD). c.2894G>A has been reported in the literature in one individual affected with neurodevelopmental disorders, microcephaly as one of the features (Wang_2023). The report does not provide unequivocal conclusions about association of the variant with Growth Delay Due To Insulin-Like Growth Factor I Resistance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37501076). ClinVar contains an entry for this variant (Variation ID: 731844). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Growth delay due to insulin-like growth factor I resistance

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.40

T;.;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.81

.;.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;.;N;.

PhyloP100

2.8

PrimateAI

Benign

0.38

PROVEAN

Benign

0.050

.;.;N;N

REVEL

Benign

0.082

Sift

Benign

0.44

.;.;T;T

Sift4G

Benign

0.49

.;.;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.041, 0.045

MutPred

0.34

Loss of stability (P = 0.0429);.;Loss of stability (P = 0.0429);.;

MVP

0.50

MPC

0.57

ClinPred

0.040

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.53

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over