chr15-98649525-C-CTTTTT

Variant names:

• chr15-98649525-C-CTTTTT
• rs544674838
• NM_000875.5:c.-37_-33dupTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000875.5(IGF1R):​c.-37_-33dupTTTTT 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 0.0030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00091 (3 hom.)
• Consequence: IGF1R NM_000875.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• Publications: 0 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.

• BS2: High Homozygotes in GnomAdExome4 at 3 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.-37_-33dupTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-37_-33dupTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1258_1262dupAAAAA		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.-37_-33dupTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-37_-33dupTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2314_83+2318dupTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 378 AN: 124434 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000742

Gnomad AMI AF: 0.00126

Gnomad AMR AF: 0.00246

Gnomad ASJ AF: 0.00694

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.000356

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00538

GnomAD4 exome AF: 0.000909 AC: 547 AN: 601466 Hom.: 3 Cov.: 0 AF XY: 0.000953 AC XY: 306 AN XY: 320960

African (AFR) AF: 0.000288 AC: 4 AN: 13902

American (AMR) AF: 0.00102 AC: 25 AN: 24496

Ashkenazi Jewish (ASJ) AF: 0.000674 AC: 11 AN: 16324

East Asian (EAS) AF: 0.000871 AC: 24 AN: 27556

South Asian (SAS) AF: 0.00262 AC: 137 AN: 52274

European-Finnish (FIN) AF: 0.000577 AC: 21 AN: 36382

Middle Eastern (MID) AF: 0.000675 AC: 2 AN: 2964

European-Non Finnish (NFE) AF: 0.000748 AC: 298 AN: 398510

Other (OTH) AF: 0.000860 AC: 25 AN: 29058

GnomAD4 genome AF: 0.00304 AC: 378 AN: 124442 Hom.: 0 Cov.: 0 AF XY: 0.00286 AC XY: 170 AN XY: 59432

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

African (AFR) AF: 0.000741 AC: 25 AN: 33726

American (AMR) AF: 0.00246 AC: 31 AN: 12590

Ashkenazi Jewish (ASJ) AF: 0.00694 AC: 21 AN: 3028

East Asian (EAS) AF: 0.00424 AC: 17 AN: 4008

South Asian (SAS) AF: 0.00231 AC: 9 AN: 3894

European-Finnish (FIN) AF: 0.000356 AC: 2 AN: 5622

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

European-Non Finnish (NFE) AF: 0.00447 AC: 263 AN: 58882

Other (OTH) AF: 0.00534 AC: 9 AN: 1684

⚠️ 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;