15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTT

Variant names:

• chr15-98649525-CTTTTTT-C
• rs544674838
• NM_000875.5:c.-38_-33delTTTTTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-38_-33delTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 724,130 control chromosomes in the GnomAD database, including 9 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0040 (7 hom.)
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00311 (388/124660) while in subpopulation AFR AF = 0.00898 (303/33740). AF 95% confidence interval is 0.00815. There are 2 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.-38_-33delTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-38_-33delTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1257_1262delAAAAAA		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.-38_-33delTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-38_-33delTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2313_83+2318delTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 388 AN: 124652 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00899

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00796

Gnomad SAS AF: 0.00179

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000288

Gnomad OTH AF: 0.00299

GnomAD4 exome AF: 0.00395 AC: 2368 AN: 599470 Hom.: 7 AF XY: 0.00410 AC XY: 1312 AN XY: 319810

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

African (AFR) AF: 0.0154 AC: 212 AN: 13776

American (AMR) AF: 0.00681 AC: 166 AN: 24392

Ashkenazi Jewish (ASJ) AF: 0.00344 AC: 56 AN: 16256

East Asian (EAS) AF: 0.00708 AC: 194 AN: 27394

South Asian (SAS) AF: 0.00767 AC: 398 AN: 51872

European-Finnish (FIN) AF: 0.000964 AC: 35 AN: 36298

Middle Eastern (MID) AF: 0.00473 AC: 14 AN: 2962

European-Non Finnish (NFE) AF: 0.00281 AC: 1116 AN: 397594

Other (OTH) AF: 0.00612 AC: 177 AN: 28926

⚠️ 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: 0.00311 AC: 388 AN: 124660 Hom.: 2 Cov.: 0 AF XY: 0.00316 AC XY: 188 AN XY: 59520

African (AFR) AF: 0.00898 AC: 303 AN: 33740

American (AMR) AF: 0.00190 AC: 24 AN: 12608

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

East Asian (EAS) AF: 0.00798 AC: 32 AN: 4010

South Asian (SAS) AF: 0.00180 AC: 7 AN: 3896

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

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

European-Non Finnish (NFE) AF: 0.000288 AC: 17 AN: 59054

Other (OTH) AF: 0.00297 AC: 5 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		=296/4	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;