15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr15-98649525-C-CTTTTTTTTTTTTTTTTTT
• rs544674838
• NM_000875.5:c.-50_-33dupTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000875.5(IGF1R):​c.-50_-33dupTTTTTTTTTTTTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: IGF1R NM_000875.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 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.-50_-33dupTTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-50_-33dupTTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1245_1262dupAAAAAAAAAAAAAAAAAA		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.-50_-33dupTTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-50_-33dupTTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2301_83+2318dupTTTTTTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000458 AC: 57 AN: 124582 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000891

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000238

Gnomad ASJ AF: 0.000660

Gnomad EAS AF: 0.000748

Gnomad SAS AF: 0.000766

Gnomad FIN AF: 0.000178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000712

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 91 AN: 601552 Hom.: 2 Cov.: 0 AF XY: 0.000171 AC XY: 55 AN XY: 321010

African (AFR) AF: 0.0000719 AC: 1 AN: 13902

American (AMR) AF: 0.0000816 AC: 2 AN: 24498

Ashkenazi Jewish (ASJ) AF: 0.000245 AC: 4 AN: 16324

East Asian (EAS) AF: 0.000109 AC: 3 AN: 27560

South Asian (SAS) AF: 0.000478 AC: 25 AN: 52282

European-Finnish (FIN) AF: 0.000137 AC: 5 AN: 36386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2964

European-Non Finnish (NFE) AF: 0.000125 AC: 50 AN: 398572

Other (OTH) AF: 0.0000344 AC: 1 AN: 29064

GnomAD4 genome AF: 0.000458 AC: 57 AN: 124590 Hom.: 0 Cov.: 0 AF XY: 0.000387 AC XY: 23 AN XY: 59492

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

African (AFR) AF: 0.0000889 AC: 3 AN: 33728

American (AMR) AF: 0.000238 AC: 3 AN: 12606

Ashkenazi Jewish (ASJ) AF: 0.000660 AC: 2 AN: 3030

East Asian (EAS) AF: 0.000750 AC: 3 AN: 4002

South Asian (SAS) AF: 0.000770 AC: 3 AN: 3894

European-Finnish (FIN) AF: 0.000178 AC: 1 AN: 5624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000712 AC: 42 AN: 59014

Other (OTH) AF: 0.00 AC: 0 AN: 1684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29

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;