15-98649525-C-CTT

Variant names:

• chr15-98649525-C-CTT
• rs544674838
• NM_000875.5:c.-34_-33dupTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-34_-33dupTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0038 (15 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00367 (457/124474) while in subpopulation AFR AF = 0.00889 (299/33624). AF 95% confidence interval is 0.00806. There are 2 homozygotes in GnomAd4. There are 212 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.-34_-33dupTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-34_-33dupTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1261_1262dupAA		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.-34_-33dupTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-34_-33dupTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2317_83+2318dupTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 457 AN: 124468 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00890

Gnomad AMI AF: 0.00126

Gnomad AMR AF: 0.000953

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00324

Gnomad SAS AF: 0.00204

Gnomad FIN AF: 0.000178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00379 AC: 2272 AN: 599102 Hom.: 15 Cov.: 0 AF XY: 0.00379 AC XY: 1211 AN XY: 319680

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

African (AFR) AF: 0.00188 AC: 26 AN: 13832

American (AMR) AF: 0.00410 AC: 100 AN: 24386

Ashkenazi Jewish (ASJ) AF: 0.00388 AC: 63 AN: 16254

East Asian (EAS) AF: 0.00432 AC: 118 AN: 27318

South Asian (SAS) AF: 0.00808 AC: 421 AN: 52126

European-Finnish (FIN) AF: 0.00314 AC: 114 AN: 36274

Middle Eastern (MID) AF: 0.00203 AC: 6 AN: 2958

European-Non Finnish (NFE) AF: 0.00332 AC: 1318 AN: 397014

Other (OTH) AF: 0.00366 AC: 106 AN: 28940

⚠️ 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: 0.00367 AC: 457 AN: 124474 Hom.: 2 Cov.: 0 AF XY: 0.00357 AC XY: 212 AN XY: 59432

African (AFR) AF: 0.00889 AC: 299 AN: 33624

American (AMR) AF: 0.000953 AC: 12 AN: 12598

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 7 AN: 3032

East Asian (EAS) AF: 0.00324 AC: 13 AN: 4008

South Asian (SAS) AF: 0.00205 AC: 8 AN: 3894

European-Finnish (FIN) AF: 0.000178 AC: 1 AN: 5622

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

European-Non Finnish (NFE) AF: 0.00190 AC: 112 AN: 59004

Other (OTH) AF: 0.00238 AC: 4 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		-0.29
Mutation Taster		=300/0	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;