15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant names:

• chr15-98649525-CTTTT-C
• rs544674838
• NM_000875.5:c.-36_-33delTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000875.5(IGF1R):​c.-36_-33delTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00984 in 721,932 control chromosomes in the GnomAD database, including 34 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (24 hom., cov: 0)
  • Exomes 𝑓: 0.0077 (10 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0199 (2480/124532) while in subpopulation AFR AF = 0.0361 (1217/33680). AF 95% confidence interval is 0.0344. There are 24 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

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.-36_-33delTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-36_-33delTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1259_1262delAAAA		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.-36_-33delTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-36_-33delTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2315_83+2318delTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 2478 AN: 124524 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00252

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0214

Gnomad EAS AF: 0.00373

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.00774 AC: 4622 AN: 597400 Hom.: 10 AF XY: 0.00773 AC XY: 2463 AN XY: 318646

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

African (AFR) AF: 0.0251 AC: 344 AN: 13692

American (AMR) AF: 0.00738 AC: 180 AN: 24380

Ashkenazi Jewish (ASJ) AF: 0.00815 AC: 132 AN: 16206

East Asian (EAS) AF: 0.00560 AC: 153 AN: 27326

South Asian (SAS) AF: 0.00938 AC: 484 AN: 51588

European-Finnish (FIN) AF: 0.00856 AC: 309 AN: 36106

Middle Eastern (MID) AF: 0.00372 AC: 11 AN: 2954

European-Non Finnish (NFE) AF: 0.00689 AC: 2729 AN: 396314

Other (OTH) AF: 0.00971 AC: 280 AN: 28834

⚠️ 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: 0.0199 AC: 2480 AN: 124532 Hom.: 24 Cov.: 0 AF XY: 0.0200 AC XY: 1190 AN XY: 59468

African (AFR) AF: 0.0361 AC: 1217 AN: 33680

American (AMR) AF: 0.0109 AC: 137 AN: 12594

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 65 AN: 3034

East Asian (EAS) AF: 0.00374 AC: 15 AN: 4012

South Asian (SAS) AF: 0.0216 AC: 84 AN: 3886

European-Finnish (FIN) AF: 0.0185 AC: 104 AN: 5612

Middle Eastern (MID) AF: 0.0234 AC: 5 AN: 214

European-Non Finnish (NFE) AF: 0.0140 AC: 824 AN: 59026

Other (OTH) AF: 0.0161 AC: 27 AN: 1680

Alfa AF: 0.0101 Hom.: 328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs544674838; hg19: chr15-99192754;