15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTT

Variant names:

• chr15-98649525-CTTTTTTTTTT-C
• rs544674838
• NM_000875.5:c.-42_-33delTTTTTTTTTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-42_-33delTTTTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 581,986 control chromosomes in the GnomAD database, including 136 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 0)
  • Exomes 𝑓: 0.050 (136 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 136 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.-42_-33delTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-42_-33delTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1253_1262delAAAAAAAAAA		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.-42_-33delTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-42_-33delTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2309_83+2318delTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000425 AC: 53 AN: 124642 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000794

Gnomad ASJ AF: 0.000329

Gnomad EAS AF: 0.000746

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.000889

Gnomad MID AF: 0.00870

Gnomad NFE AF: 0.000508

Gnomad OTH AF: 0.000598

GnomAD4 exome AF: 0.0505 AC: 29381 AN: 581986 Hom.: 136 AF XY: 0.0487 AC XY: 15102 AN XY: 310288

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

African (AFR) AF: 0.0176 AC: 240 AN: 13660

American (AMR) AF: 0.0393 AC: 941 AN: 23936

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 482 AN: 15898

East Asian (EAS) AF: 0.0409 AC: 1077 AN: 26310

South Asian (SAS) AF: 0.0353 AC: 1804 AN: 51116

European-Finnish (FIN) AF: 0.0547 AC: 1890 AN: 34542

Middle Eastern (MID) AF: 0.0531 AC: 151 AN: 2844

European-Non Finnish (NFE) AF: 0.0560 AC: 21582 AN: 385624

Other (OTH) AF: 0.0433 AC: 1214 AN: 28056

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000425 AC: 53 AN: 124650 Hom.: 1 Cov.: 0 AF XY: 0.000403 AC XY: 24 AN XY: 59516

African (AFR) AF: 0.000148 AC: 5 AN: 33738

American (AMR) AF: 0.0000793 AC: 1 AN: 12608

Ashkenazi Jewish (ASJ) AF: 0.000329 AC: 1 AN: 3036

East Asian (EAS) AF: 0.000748 AC: 3 AN: 4012

South Asian (SAS) AF: 0.00128 AC: 5 AN: 3896

European-Finnish (FIN) AF: 0.000889 AC: 5 AN: 5624

Middle Eastern (MID) AF: 0.00935 AC: 2 AN: 214

European-Non Finnish (NFE) AF: 0.000508 AC: 30 AN: 59044

Other (OTH) AF: 0.000594 AC: 1 AN: 1684

Alfa AF: 0.00 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

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

Other links and lift over

dbSNP: rs544674838; hg19: chr15-99192754;