dbSNP rs2229764: IGF1R:p.Gly301Gly (chr15-98891587-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000875.5(IGF1R):c.903C>A(p.Gly301Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,604,766 control chromosomes in the GnomAD database, including 555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G301G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 38 hom., cov: 32)

Exomes 𝑓: 0.023 ( 517 hom. )

Consequence

IGF1R
NM_000875.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.536

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, Orphanet, Labcorp Genetics (formerly Invitae)

IGF1R links:

ENSG00000259621 (HGNC:58474):

ENSG00000259621 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 15-98891587-C-A is Benign according to our data. Variant chr15-98891587-C-A is described in ClinVar as Benign. ClinVar VariationId is 317444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.536 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0168 (2565/152310) while in subpopulation SAS AF = 0.0396 (191/4820). AF 95% confidence interval is 0.035. There are 38 homozygotes in GnomAd4. There are 1226 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.903C>A	p.Gly301Gly	synonymous	Exon 3 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.903C>A	p.Gly301Gly	synonymous	Exon 3 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGF1R	ENST00000650285.1	MANE Select	c.903C>A	p.Gly301Gly	synonymous	Exon 3 of 21	ENSP00000497069.1	P08069
IGF1R	ENST00000559925.5	TSL:1	n.903C>A		non_coding_transcript_exon	Exon 3 of 10
IGF1R	ENST00000649865.1		c.903C>A	p.Gly301Gly	synonymous	Exon 3 of 21	ENSP00000496919.1	C9J5X1

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2564

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00405

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0573

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0394

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0229

AC:

5579

AN:

243976

AF XY:

0.0253

show subpopulations

Gnomad AFR exome

AF:

0.00365

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0500

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0238

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0227

AC:

32965

AN:

1452456

Hom.:

517

Cov.:

AF XY:

0.0239

AC XY:

17295

AN XY:

722868

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

33474

American (AMR)

AF:

0.0110

AC:

492

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0502

AC:

1311

AN:

26124

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0480

AC:

4138

AN:

86244

European-Finnish (FIN)

AF:

0.0189

AC:

837

AN:

44174

Middle Eastern (MID)

AF:

0.0383

AC:

221

AN:

5768

European-Non Finnish (NFE)

AF:

0.0220

AC:

24444

AN:

1111930

Other (OTH)

AF:

0.0235

AC:

1420

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1884

3768

5653

7537

9421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

922

1844

2766

3688

4610

<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:

0.0168

AC:

2565

AN:

152310

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1226

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00404

AC:

168

AN:

41586

American (AMR)

AF:

0.0108

AC:

166

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

199

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0396

AC:

191

AN:

4820

European-Finnish (FIN)

AF:

0.0179

AC:

190

AN:

10608

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0230

AC:

1562

AN:

68014

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

141

282

424

565

706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0206

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0271

EpiControl

AF:

0.0258

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Growth delay due to insulin-like growth factor I resistance (1)

IGF1R-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

8.1

(source)

DANN

Benign

0.89

PhyloP100

-0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over