NM_000875.5:c.2570A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000875.5(IGF1R):c.2570A>G(p.Asn857Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,614,050 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 13 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.90

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041776896).

BP6

Variant 15-98923960-A-G is Benign according to our data. Variant chr15-98923960-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000926 (141/152338) while in subpopulation EAS AF = 0.0202 (105/5188). AF 95% confidence interval is 0.0171. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.2570A>G	p.Asn857Ser	missense	Exon 12 of 21	NP_000866.1
	IGF1R	NM_001291858.2		c.2570A>G	p.Asn857Ser	missense	Exon 12 of 21	NP_001278787.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IGF1R	ENST00000650285.1	MANE Select	c.2570A>G	p.Asn857Ser	missense	Exon 12 of 21	ENSP00000497069.1
IGF1R	ENST00000649865.1		c.2570A>G	p.Asn857Ser	missense	Exon 12 of 21	ENSP00000496919.1
IGF1R	ENST00000560343.1	TSL:3	n.179A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0202

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00214

AC:

538

AN:

251494

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0253

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000660

AC:

964

AN:

1461712

Hom.:

Cov.:

AF XY:

0.000710

AC XY:

516

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0169

AC:

672

AN:

39700

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1111844

Other (OTH)

AF:

0.000894

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000926

AC:

141

AN:

152338

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0202

AC:

105

AN:

5188

South Asian (SAS)

AF:

0.00165

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68038

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00105

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00203

AC:

247

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 13, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IGF1R: BS1, BS2

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Nov 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Growth delay due to insulin-like growth factor I resistance

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.28

PhyloP100

1.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.54

REVEL

Benign

0.061

Sift

Benign

0.51

Sift4G

Benign

0.83

Polyphen

0.0050

Vest4

0.088

MVP

0.51

MPC

0.49

ClinPred

0.010

GERP RS

5.8

Varity_R

0.085

gMVP

0.34

Mutation Taster

=97/3

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over