chr15-98649539-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_000875.5(IGF1R):​c.-43T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 147,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00061 ( 4 hom. )
Failed GnomAD Quality Control

Consequence

IGF1R
NM_000875.5 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.859
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000523 (77/147274) while in subpopulation NFE AF= 0.000994 (66/66400). AF 95% confidence interval is 0.000801. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IGF1RNM_000875.5 linkuse as main transcriptc.-43T>C 5_prime_UTR_variant 1/21 ENST00000650285.1
IRAINNR_126453.2 linkuse as main transcriptn.1249A>G non_coding_transcript_exon_variant 1/1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IGF1RENST00000650285.1 linkuse as main transcriptc.-43T>C 5_prime_UTR_variant 1/21 NM_000875.5 P4
IGF1RENST00000649865.1 linkuse as main transcriptc.-43T>C 5_prime_UTR_variant 1/21 A1
IGF1RENST00000559925.5 linkuse as main transcript upstream_gene_variant 1

Frequencies

GnomAD3 genomes
AF:
0.000523
AC:
77
AN:
147208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000197
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000671
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000210
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000994
Gnomad OTH
AF:
0.000495
GnomAD3 exomes
AF:
0.000580
AC:
76
AN:
130974
Hom.:
0
AF XY:
0.000683
AC XY:
50
AN XY:
73258
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000198
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000238
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00110
Gnomad OTH exome
AF:
0.000314
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000606
AC:
522
AN:
861786
Hom.:
4
Cov.:
12
AF XY:
0.000563
AC XY:
252
AN XY:
447236
show subpopulations
Gnomad4 AFR exome
AF:
0.000199
Gnomad4 AMR exome
AF:
0.000295
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000942
Gnomad4 FIN exome
AF:
0.0000231
Gnomad4 NFE exome
AF:
0.000795
Gnomad4 OTH exome
AF:
0.000456
GnomAD4 genome
AF:
0.000523
AC:
77
AN:
147274
Hom.:
0
Cov.:
33
AF XY:
0.000446
AC XY:
32
AN XY:
71732
show subpopulations
Gnomad4 AFR
AF:
0.000197
Gnomad4 AMR
AF:
0.0000670
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000210
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000994
Gnomad4 OTH
AF:
0.000491
Alfa
AF:
0.000843
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.51
CADD
Benign
14
DANN
Benign
0.90

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: rs768733704; hg19: chr15-99192768; API