rs45493995

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: 2.79
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2
Missense variant in the IGF1R gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: 4.6449 (above the threshold of 3.09). GenCC associations: The gene is linked to growth delay due to insulin-like growth factor I resistance.
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 id is 731844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IGF1RNM_000875.5 linkc.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 Appris UniProt
IGF1RENST00000650285.1 linkc.2894G>A p.Ser965Asn missense_variant Exon 15 of 21 NM_000875.5 ENSP00000497069.1 P08069
IGF1RENST00000560972.1 linkn.197G>A non_coding_transcript_exon_variant Exon 3 of 4 1
IGF1RENST00000649865.1 linkc.2891G>A p.Ser964Asn missense_variant Exon 15 of 21 ENSP00000496919.1 C9J5X1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152246
Hom.:
0
Cov.:
33
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
GnomAD3 exomes
AF:
0.000124
AC:
31
AN:
250604
Hom.:
0
AF XY:
0.0000591
AC XY:
8
AN XY:
135414
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1460518
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
726604
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000630
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152364
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
ExAC
AF:
0.000132
AC:
16

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
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
17
DANN
Benign
0.92
DEOGEN2
Benign
0.40
T;.;T;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.81
.;.;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.010
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.4
N;.;N;.
PrimateAI
Benign
0.38
T
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
T
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.020
gMVP
0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs45493995; hg19: chr15-99473472; COSMIC: COSV105088932; API