rs45495500

Positions:

• chr15-98935311-C-T

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.3187-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,538,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: IGF1R NM_000875.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001913
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.733

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000541 (82/151568) while in subpopulation SAS AF= 0.00125 (6/4790). AF 95% confidence interval is 0.000545. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 31. 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.3187-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3187-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000560972.1	n.260-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
IGF1R	ENST00000649865.1	c.3184-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000496919	A1

Frequencies

GnomAD3 genomes AF: 0.000541 AC: 82 AN: 151450 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000857

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000895 AC: 140 AN: 156356 Hom.: 0 AF XY: 0.000851 AC XY: 70 AN XY: 82226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000525

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.000130

Gnomad NFE exome AF: 0.000944

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.000647 AC: 898 AN: 1386986 Hom.: 1 Cov.: 31 AF XY: 0.000679 AC XY: 465 AN XY: 684818

Gnomad4 AFR exome AF: 0.000160

Gnomad4 AMR exome AF: 0.000364

Gnomad4 ASJ exome AF: 0.00351

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.000264

Gnomad4 NFE exome AF: 0.000556

Gnomad4 OTH exome AF: 0.000955

GnomAD4 genome AF: 0.000541 AC: 82 AN: 151568 Hom.: 0 Cov.: 31 AF XY: 0.000527 AC XY: 39 AN XY: 73974

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000856

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000692

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000939 Hom.: 0

Bravo AF: 0.000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -

not specified Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2023	Variant summary: IGF1R c.3187-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0009 in 156356 control chromosomes. To our knowledge, no occurrence of c.3187-5C>T in individuals affected with Growth Delay Due To Insulin-Like Growth Factor I Resistance and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n-2) or benign (n=1). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 16, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.4
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		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: rs45495500; hg19: chr15-99478540; COSMIC: COSV51269613;