rs34516635
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_000875.5(IGF1R):c.1310G>A(p.Arg437His) variant causes a missense change. The variant allele was found at a frequency of 0.00355 in 1,614,058 control chromosomes in the GnomAD database, including 17 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 0.0028 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0036 ( 16 hom. )
Consequence
IGF1R
NM_000875.5 missense
NM_000875.5 missense
Scores
1
13
Clinical Significance
Conservation
PhyloP100: 3.98
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, IGF1R
BP4
?
Computational evidence support a benign effect (MetaRNN=0.008615285).
BP6
?
Variant 15-98908747-G-A is Benign according to our data. Variant chr15-98908747-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98908747-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00279 (425/152254) while in subpopulation NFE AF= 0.00448 (305/68030). AF 95% confidence interval is 0.00407. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 16 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IGF1R | NM_000875.5 | c.1310G>A | p.Arg437His | missense_variant | 6/21 | ENST00000650285.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGF1R | ENST00000650285.1 | c.1310G>A | p.Arg437His | missense_variant | 6/21 | NM_000875.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00279 AC: 425AN: 152136Hom.: 1 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
425
AN:
152136
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00314 AC: 790AN: 251266Hom.: 2 AF XY: 0.00322 AC XY: 438AN XY: 135832
GnomAD3 exomes
AF:
AC:
790
AN:
251266
Hom.:
AF XY:
AC XY:
438
AN XY:
135832
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00363 AC: 5311AN: 1461804Hom.: 16 Cov.: 32 AF XY: 0.00371 AC XY: 2697AN XY: 727202
GnomAD4 exome
AF:
AC:
5311
AN:
1461804
Hom.:
Cov.:
32
AF XY:
AC XY:
2697
AN XY:
727202
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00279 AC: 425AN: 152254Hom.: 1 Cov.: 33 AF XY: 0.00265 AC XY: 197AN XY: 74450
GnomAD4 genome
?
AF:
AC:
425
AN:
152254
Hom.:
Cov.:
33
AF XY:
AC XY:
197
AN XY:
74450
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
14
ALSPAC
AF:
AC:
15
ESP6500AA
AF:
AC:
4
ESP6500EA
AF:
AC:
43
ExAC
?
AF:
AC:
390
Asia WGS
AF:
AC:
2
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | IGF1R: BP4, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 17, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 01, 2014 | - - |
Growth delay due to insulin-like growth factor I resistance Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
IGF1R-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 25, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;N;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
Polyphen
B;B;B;B;.
Vest4
0.10, 0.11
MVP
0.54
MPC
0.77
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at