chr15-98649525-CTTTTTTT-C

Variant names:

• chr15-98649525-CTTTTTTT-C
• rs544674838
• NM_000875.5:c.-39_-33delTTTTTTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-39_-33delTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 721,818 control chromosomes in the GnomAD database, including 32 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0083 (31 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 = 0.00275 (343/124616) while in subpopulation AFR AF = 0.0081 (273/33710). AF 95% confidence interval is 0.00731. There are 1 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 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.-39_-33delTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-39_-33delTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1256_1262delAAAAAAA		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.-39_-33delTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-39_-33delTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2312_83+2318delTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 343 AN: 124608 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000555

Gnomad ASJ AF: 0.000988

Gnomad EAS AF: 0.00373

Gnomad SAS AF: 0.000255

Gnomad FIN AF: 0.000178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000610

Gnomad OTH AF: 0.00419

GnomAD4 exome AF: 0.00834 AC: 4978 AN: 597202 Hom.: 31 AF XY: 0.00799 AC XY: 2547 AN XY: 318694

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

African (AFR) AF: 0.0399 AC: 545 AN: 13666

American (AMR) AF: 0.00677 AC: 165 AN: 24366

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 175 AN: 16156

East Asian (EAS) AF: 0.00430 AC: 118 AN: 27458

South Asian (SAS) AF: 0.00605 AC: 313 AN: 51706

European-Finnish (FIN) AF: 0.00182 AC: 66 AN: 36224

Middle Eastern (MID) AF: 0.00984 AC: 29 AN: 2946

European-Non Finnish (NFE) AF: 0.00833 AC: 3296 AN: 395884

Other (OTH) AF: 0.00941 AC: 271 AN: 28796

⚠️ 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: 0.00275 AC: 343 AN: 124616 Hom.: 1 Cov.: 0 AF XY: 0.00282 AC XY: 168 AN XY: 59498

African (AFR) AF: 0.00810 AC: 273 AN: 33710

American (AMR) AF: 0.000555 AC: 7 AN: 12610

Ashkenazi Jewish (ASJ) AF: 0.000988 AC: 3 AN: 3036

East Asian (EAS) AF: 0.00374 AC: 15 AN: 4012

South Asian (SAS) AF: 0.000257 AC: 1 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: 0.000610 AC: 36 AN: 59038

Other (OTH) AF: 0.00416 AC: 7 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		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;