NM_000875.5:c.-49_-33dupTTTTTTTTTTTTTTTTT

Variant names:

• chr15-98649525-C-CTTTTTTTTTTTTTTTTT
• rs544674838
• NM_000875.5:c.-49_-33dupTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_000875.5(IGF1R):​c.-49_-33dupTTTTTTTTTTTTTTTTT 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 0.000032 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000071 (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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000715 (43/601552) while in subpopulation SAS AF = 0.000191 (10/52284). AF 95% confidence interval is 0.000103. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

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.-49_-33dupTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-49_-33dupTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1246_1262dupAAAAAAAAAAAAAAAAA		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.-49_-33dupTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-49_-33dupTTTTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2302_83+2318dupTTTTTTTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000321 AC: 4 AN: 124648 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000508

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000715 AC: 43 AN: 601552 Hom.: 0 Cov.: 0 AF XY: 0.0000779 AC XY: 25 AN XY: 321012

African (AFR) AF: 0.00 AC: 0 AN: 13902

American (AMR) AF: 0.0000408 AC: 1 AN: 24498

Ashkenazi Jewish (ASJ) AF: 0.000184 AC: 3 AN: 16324

East Asian (EAS) AF: 0.00 AC: 0 AN: 27560

South Asian (SAS) AF: 0.000191 AC: 10 AN: 52284

European-Finnish (FIN) AF: 0.000110 AC: 4 AN: 36386

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

European-Non Finnish (NFE) AF: 0.0000627 AC: 25 AN: 398570

Other (OTH) AF: 0.00 AC: 0 AN: 29064

GnomAD4 genome AF: 0.0000321 AC: 4 AN: 124648 Hom.: 0 Cov.: 0 AF XY: 0.0000168 AC XY: 1 AN XY: 59496

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

African (AFR) AF: 0.0000297 AC: 1 AN: 33690

American (AMR) AF: 0.00 AC: 0 AN: 12598

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4022

South Asian (SAS) AF: 0.00 AC: 0 AN: 3920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.0000508 AC: 3 AN: 59062

Other (OTH) AF: 0.00 AC: 0 AN: 1672

⚠️ 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;