NM_000875.5:c.-35_-33dupTTT

Variant names:

• chr15-98649525-C-CTTT
• rs544674838
• NM_000875.5:c.-35_-33dupTTT

Variant summary

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

The NM_000875.5(IGF1R):​c.-35_-33dupTTT 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 0.00030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (6 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 6 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.-35_-33dupTTT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-35_-33dupTTT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1260_1262dupAAA		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.-35_-33dupTTT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-35_-33dupTTT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2316_83+2318dupTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 37 AN: 124636 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000746

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000237

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00194 AC: 1167 AN: 600818 Hom.: 6 Cov.: 0 AF XY: 0.00208 AC XY: 668 AN XY: 320568

African (AFR) AF: 0.000864 AC: 12 AN: 13884

American (AMR) AF: 0.00310 AC: 76 AN: 24482

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 40 AN: 16296

East Asian (EAS) AF: 0.00175 AC: 48 AN: 27492

South Asian (SAS) AF: 0.00477 AC: 249 AN: 52194

European-Finnish (FIN) AF: 0.00173 AC: 63 AN: 36358

Middle Eastern (MID) AF: 0.00135 AC: 4 AN: 2954

European-Non Finnish (NFE) AF: 0.00155 AC: 617 AN: 398112

Other (OTH) AF: 0.00200 AC: 58 AN: 29046

GnomAD4 genome AF: 0.000297 AC: 37 AN: 124644 Hom.: 0 Cov.: 0 AF XY: 0.000286 AC XY: 17 AN XY: 59514

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

African (AFR) AF: 0.000593 AC: 20 AN: 33728

American (AMR) AF: 0.00 AC: 0 AN: 12608

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

East Asian (EAS) AF: 0.000748 AC: 3 AN: 4012

South Asian (SAS) AF: 0.00 AC: 0 AN: 3896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5624

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

European-Non Finnish (NFE) AF: 0.000237 AC: 14 AN: 59048

Other (OTH) AF: 0.00 AC: 0 AN: 1684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000160772), which strongly suggests a high chance of mosaicism in these individuals.

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

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;