15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Variant names:

• chr15-98649525-CTTTTT-C
• rs544674838
• NM_000875.5:c.-37_-33delTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000875.5(IGF1R):​c.-37_-33delTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 722,040 control chromosomes in the GnomAD database, including 141 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.042 (114 hom., cov: 0)
  • Exomes 𝑓: 0.016 (27 hom.)
• Consequence: IGF1R NM_000875.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 2 publications found

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:50365): (IGF1R antisense imprinted non-protein coding RNA) This gene expresses a long non-coding RNA in antisense to the insulin-like growth factor type I receptor (IGF1R) gene. This transcript is imprinted and expressed from the paternal allele. It interacts with chromatin and may promote long-range DNA interactions that influence the regulation of gene expression. [provided by RefSeq, Nov 2015]

ENSG00000278022 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.-37_-33delTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-37_-33delTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1258_1262delAAAAA		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.-37_-33delTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-37_-33delTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2314_83+2318delTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 5226 AN: 124602 Hom.: 114 Cov.: 0

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.00504

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0359

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0443

GnomAD4 exome AF: 0.0162 AC: 9683 AN: 597430 Hom.: 27 AF XY: 0.0165 AC XY: 5262 AN XY: 318600

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0353 AC: 484 AN: 13712

American (AMR) AF: 0.0198 AC: 480 AN: 24300

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 267 AN: 16218

East Asian (EAS) AF: 0.0351 AC: 952 AN: 27146

South Asian (SAS) AF: 0.0278 AC: 1431 AN: 51456

European-Finnish (FIN) AF: 0.00806 AC: 292 AN: 36214

Middle Eastern (MID) AF: 0.00848 AC: 25 AN: 2948

European-Non Finnish (NFE) AF: 0.0130 AC: 5171 AN: 396620

Other (OTH) AF: 0.0202 AC: 581 AN: 28816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0419 AC: 5227 AN: 124610 Hom.: 114 Cov.: 0 AF XY: 0.0436 AC XY: 2592 AN XY: 59492

African (AFR) AF: 0.0667 AC: 2251 AN: 33728

American (AMR) AF: 0.0485 AC: 611 AN: 12598

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 109 AN: 3034

East Asian (EAS) AF: 0.0870 AC: 349 AN: 4010

South Asian (SAS) AF: 0.0979 AC: 380 AN: 3882

European-Finnish (FIN) AF: 0.0128 AC: 72 AN: 5622

Middle Eastern (MID) AF: 0.0140 AC: 3 AN: 214

European-Non Finnish (NFE) AF: 0.0233 AC: 1373 AN: 59044

Other (OTH) AF: 0.0445 AC: 75 AN: 1684

Alfa AF: 0.00562 Hom.: 328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=283/17	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs544674838; hg19: chr15-99192754;