15-98649539-T-C

Position:

• chr15-98649539-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

IRAIN (HGNC:):

ACMG classification

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	Protein	UniProt
IGF1R	NM_000875.5	c.-43T>C		5_prime_UTR_variant	1/21	ENST00000650285.1	NP_000866.1
IRAIN	NR_126453.2	n.1249A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.-43T>C		5_prime_UTR_variant	1/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000649865.1	c.-43T>C		5_prime_UTR_variant	1/21			ENSP00000496919	A1
IGF1R	ENST00000559925.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000523 AC: 77 AN: 147208 Hom.: 0 Cov.: 33

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

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

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

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

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

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

Other links and lift over

dbSNP: rs768733704; hg19: chr15-99192768;