15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTT

Variant names:

• chr15-98649525-CTT-C
• rs544674838
• NM_000875.5:c.-34_-33delTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-34_-33delTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 721,928 control chromosomes in the GnomAD database, including 7 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 0)
  • Exomes 𝑓: 0.0050 (0 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 afr. GnomAd4 allele frequency = 0.00735 (916/124562) while in subpopulation AFR AF = 0.0248 (836/33648). AF 95% confidence interval is 0.0234. There are 7 homozygotes in GnomAd4. There are 444 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.-34_-33delTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-34_-33delTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1261_1262delAA		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.-34_-33delTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-34_-33delTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2317_83+2318delTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 915 AN: 124556 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000249

Gnomad SAS AF: 0.00102

Gnomad FIN AF: 0.000178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00539

GnomAD4 exome AF: 0.00503 AC: 3004 AN: 597366 Hom.: 0 AF XY: 0.00496 AC XY: 1582 AN XY: 318840

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

African (AFR) AF: 0.0121 AC: 166 AN: 13732

American (AMR) AF: 0.00423 AC: 103 AN: 24360

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 98 AN: 16184

East Asian (EAS) AF: 0.0135 AC: 365 AN: 26962

South Asian (SAS) AF: 0.00184 AC: 96 AN: 52130

European-Finnish (FIN) AF: 0.00537 AC: 194 AN: 36138

Middle Eastern (MID) AF: 0.00340 AC: 10 AN: 2944

European-Non Finnish (NFE) AF: 0.00449 AC: 1779 AN: 396124

Other (OTH) AF: 0.00670 AC: 193 AN: 28792

⚠️ 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: 0.00735 AC: 916 AN: 124562 Hom.: 7 Cov.: 0 AF XY: 0.00746 AC XY: 444 AN XY: 59484

African (AFR) AF: 0.0248 AC: 836 AN: 33648

American (AMR) AF: 0.00444 AC: 56 AN: 12606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3036

East Asian (EAS) AF: 0.000249 AC: 1 AN: 4012

South Asian (SAS) AF: 0.00103 AC: 4 AN: 3896

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: 0.000152 AC: 9 AN: 59050

Other (OTH) AF: 0.00535 AC: 9 AN: 1682

Alfa AF: 0.00 Hom.: 328

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
Mutation Taster		=295/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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;