15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

• chr15-98649525-CTTTTTTTTT-C
• rs544674838
• NM_000875.5:c.-41_-33delTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000875.5(IGF1R):​c.-41_-33delTTTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 715,492 control chromosomes in the GnomAD database, including 17,858 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (8308 hom., cov: 0)
  • Exomes 𝑓: 0.36 (9550 hom.)
• Consequence: IGF1R NM_000875.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 15-98649525-CTTTTTTTTT-C is Benign according to our data. Variant chr15-98649525-CTTTTTTTTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

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.-41_-33delTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-41_-33delTTTTTTTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1254_1262delAAAAAAAAA		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.-41_-33delTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-41_-33delTTTTTTTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2310_83+2318delTTTTTTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.359 AC: 44851 AN: 124932 Hom.: 8308 Cov.: 0

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.360 AC: 212862 AN: 590552 Hom.: 9550 AF XY: 0.357 AC XY: 112240 AN XY: 314618

African (AFR) AF: 0.171 AC: 2316 AN: 13514

American (AMR) AF: 0.275 AC: 6606 AN: 24010

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 4603 AN: 15860

East Asian (EAS) AF: 0.339 AC: 9268 AN: 27352

South Asian (SAS) AF: 0.304 AC: 15169 AN: 49930

European-Finnish (FIN) AF: 0.372 AC: 13274 AN: 35682

Middle Eastern (MID) AF: 0.385 AC: 1124 AN: 2920

European-Non Finnish (NFE) AF: 0.384 AC: 150778 AN: 392694

Other (OTH) AF: 0.340 AC: 9724 AN: 28590

GnomAD4 genome AF: 0.359 AC: 44841 AN: 124940 Hom.: 8308 Cov.: 0 AF XY: 0.366 AC XY: 21874 AN XY: 59692

African (AFR) AF: 0.144 AC: 4849 AN: 33788

American (AMR) AF: 0.363 AC: 4588 AN: 12638

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 999 AN: 3036

East Asian (EAS) AF: 0.426 AC: 1712 AN: 4020

South Asian (SAS) AF: 0.396 AC: 1546 AN: 3904

European-Finnish (FIN) AF: 0.614 AC: 3467 AN: 5648

Middle Eastern (MID) AF: 0.463 AC: 99 AN: 214

European-Non Finnish (NFE) AF: 0.449 AC: 26591 AN: 59208

Other (OTH) AF: 0.348 AC: 586 AN: 1686

Alfa AF: 0.225 Hom.: 328

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Growth delay due to insulin-like growth factor I resistance (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=296/4	polymorphism (auto)

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; COSMIC: COSV107265679; COSMIC: COSV107265679;