15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTT

Variant names:

• chr15-98649525-CTTTTTTTT-C
• rs544674838
• NM_000875.5:c.-40_-33delTTTTTTTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-40_-33delTTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 708,360 control chromosomes in the GnomAD database, including 4,427 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3158 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1269 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 (AFR) allele frequency at 95% confidence interval = 0.402 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.-40_-33delTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-40_-33delTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1255_1262delAAAAAAAA		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.-40_-33delTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-40_-33delTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2311_83+2318delTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.200 AC: 25007 AN: 124748 Hom.: 3158 Cov.: 0

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.00373

Gnomad SAS AF: 0.0842

Gnomad FIN AF: 0.0391

Gnomad MID AF: 0.254

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.134 AC: 78050 AN: 583604 Hom.: 1269 AF XY: 0.131 AC XY: 40630 AN XY: 310808

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

African (AFR) AF: 0.313 AC: 4281 AN: 13692

American (AMR) AF: 0.0934 AC: 2239 AN: 23974

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 2675 AN: 15732

East Asian (EAS) AF: 0.0316 AC: 846 AN: 26748

South Asian (SAS) AF: 0.0785 AC: 3915 AN: 49872

European-Finnish (FIN) AF: 0.0666 AC: 2333 AN: 35016

Middle Eastern (MID) AF: 0.178 AC: 511 AN: 2878

European-Non Finnish (NFE) AF: 0.147 AC: 57012 AN: 387492

Other (OTH) AF: 0.150 AC: 4238 AN: 28200

⚠️ 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: 0.201 AC: 25018 AN: 124756 Hom.: 3158 Cov.: 0 AF XY: 0.193 AC XY: 11524 AN XY: 59576

African (AFR) AF: 0.408 AC: 13806 AN: 33832

American (AMR) AF: 0.165 AC: 2075 AN: 12610

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 590 AN: 3032

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

South Asian (SAS) AF: 0.0842 AC: 328 AN: 3896

European-Finnish (FIN) AF: 0.0391 AC: 220 AN: 5626

Middle Eastern (MID) AF: 0.264 AC: 57 AN: 216

European-Non Finnish (NFE) AF: 0.126 AC: 7463 AN: 59052

Other (OTH) AF: 0.187 AC: 316 AN: 1688

Alfa AF: 0.0259 Hom.: 328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=288/12	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;