chr15-98649525-CTTTTTTTTTTT-C

Variant names:

• chr15-98649525-CTTTTTTTTTTT-C
• rs544674838
• NM_000875.5:c.-43_-33delTTTTTTTTTTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-43_-33delTTTTTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 718,688 control chromosomes in the GnomAD database, including 13 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.00033 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0058 (12 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 sas. GnomAd4 allele frequency = 0.000329 (41/124652) while in subpopulation SAS AF = 0.00205 (8/3896). AF 95% confidence interval is 0.00102. There are 1 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.-43_-33delTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-43_-33delTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1252_1262delAAAAAAAAAAA		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.-43_-33delTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-43_-33delTTTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2308_83+2318delTTTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 41 AN: 124644 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00204

Gnomad FIN AF: 0.000178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000677

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00581 AC: 3454 AN: 594036 Hom.: 12 AF XY: 0.00562 AC XY: 1782 AN XY: 317030

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

African (AFR) AF: 0.00413 AC: 57 AN: 13816

American (AMR) AF: 0.00609 AC: 148 AN: 24296

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 60 AN: 16160

East Asian (EAS) AF: 0.00309 AC: 84 AN: 27212

South Asian (SAS) AF: 0.00559 AC: 290 AN: 51844

European-Finnish (FIN) AF: 0.00565 AC: 202 AN: 35740

Middle Eastern (MID) AF: 0.00477 AC: 14 AN: 2936

European-Non Finnish (NFE) AF: 0.00623 AC: 2451 AN: 393322

Other (OTH) AF: 0.00515 AC: 148 AN: 28710

⚠️ 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: 0.000329 AC: 41 AN: 124652 Hom.: 1 Cov.: 0 AF XY: 0.000437 AC XY: 26 AN XY: 59516

African (AFR) AF: 0.000771 AC: 26 AN: 33738

American (AMR) AF: 0.000159 AC: 2 AN: 12608

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4012

South Asian (SAS) AF: 0.00205 AC: 8 AN: 3896

European-Finnish (FIN) AF: 0.000178 AC: 1 AN: 5618

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

European-Non Finnish (NFE) AF: 0.0000677 AC: 4 AN: 59052

Other (OTH) AF: 0.00 AC: 0 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;