chr15-98649539-T-C
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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
NM_000875.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.859
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 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 |
---|---|---|---|---|---|---|---|
IGF1R | NM_000875.5 | c.-43T>C | 5_prime_UTR_variant | 1/21 | ENST00000650285.1 | ||
IRAIN | NR_126453.2 | n.1249A>G | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGF1R | ENST00000650285.1 | c.-43T>C | 5_prime_UTR_variant | 1/21 | NM_000875.5 | P4 | |||
IGF1R | ENST00000649865.1 | c.-43T>C | 5_prime_UTR_variant | 1/21 | A1 | ||||
IGF1R | ENST00000559925.5 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.000523 AC: 77AN: 147208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000580 AC: 76AN: 130974Hom.: 0 AF XY: 0.000683 AC XY: 50AN XY: 73258
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000606 AC: 522AN: 861786Hom.: 4 Cov.: 12 AF XY: 0.000563 AC XY: 252AN XY: 447236
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GnomAD4 genome AF: 0.000523 AC: 77AN: 147274Hom.: 0 Cov.: 33 AF XY: 0.000446 AC XY: 32AN XY: 71732
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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 submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at