NM_000875.5:c.-33dupT

Variant names:

• chr15-98649525-C-CT
• rs544674838
• NM_000875.5:c.-33dupT

Variant summary

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

The NM_000875.5(IGF1R):​c.-33dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 0)
  • Exomes 𝑓: 0.0096 (57 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0151 (1879/124266) while in subpopulation EAS AF = 0.0515 (205/3984). AF 95% confidence interval is 0.0457. There are 20 homozygotes in GnomAd4. There are 889 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.-33dupT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-33dupT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1262dupA		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.-33dupT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-33dupT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2318dupT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 1880 AN: 124258 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.00609

Gnomad AMI AF: 0.00380

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.0513

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.00249

Gnomad MID AF: 0.00431

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00961 AC: 5721 AN: 595470 Hom.: 57 Cov.: 0 AF XY: 0.00988 AC XY: 3140 AN XY: 317794

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

African (AFR) AF: 0.00268 AC: 37 AN: 13828

American (AMR) AF: 0.00810 AC: 197 AN: 24312

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 168 AN: 16124

East Asian (EAS) AF: 0.0169 AC: 456 AN: 27020

South Asian (SAS) AF: 0.0149 AC: 776 AN: 51998

European-Finnish (FIN) AF: 0.00786 AC: 283 AN: 36018

Middle Eastern (MID) AF: 0.00511 AC: 15 AN: 2936

European-Non Finnish (NFE) AF: 0.00895 AC: 3531 AN: 394510

Other (OTH) AF: 0.00898 AC: 258 AN: 28724

⚠️ 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: 0.0151 AC: 1879 AN: 124266 Hom.: 20 Cov.: 0 AF XY: 0.0150 AC XY: 889 AN XY: 59354

African (AFR) AF: 0.00605 AC: 204 AN: 33694

American (AMR) AF: 0.0110 AC: 139 AN: 12580

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 72 AN: 3026

East Asian (EAS) AF: 0.0515 AC: 205 AN: 3984

South Asian (SAS) AF: 0.0222 AC: 86 AN: 3868

European-Finnish (FIN) AF: 0.00249 AC: 14 AN: 5612

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0192 AC: 1127 AN: 58814

Other (OTH) AF: 0.0166 AC: 28 AN: 1682

Alfa AF: 0.00718 Hom.: 328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;