chr15-98649525-CT-C

Variant names:

• chr15-98649525-CT-C
• rs544674838
• NM_000875.5:c.-33delT

Variant summary

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

The NM_000875.5(IGF1R):​c.-33delT 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 0.013 (4 hom., cov: 0)
  • Exomes 𝑓: 0.011 (0 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 GnomAd4 at 4 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.-33delT		5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.-33delT		5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
	IRAIN	NR_126453.2		n.1262delA		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.-33delT		5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.-33delT		5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
	ENSG00000278022	ENST00000747447.1		n.83+2318delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1587 AN: 124410 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.0364

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00791

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0200

Gnomad FIN AF: 0.000889

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00598

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0107 AC: 6340 AN: 594748 Hom.: 0 Cov.: 0 AF XY: 0.0106 AC XY: 3367 AN XY: 317374

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

African (AFR) AF: 0.0110 AC: 151 AN: 13756

American (AMR) AF: 0.00797 AC: 194 AN: 24332

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 214 AN: 16100

East Asian (EAS) AF: 0.0310 AC: 827 AN: 26708

South Asian (SAS) AF: 0.00493 AC: 257 AN: 52128

European-Finnish (FIN) AF: 0.0103 AC: 371 AN: 35892

Middle Eastern (MID) AF: 0.00854 AC: 25 AN: 2928

European-Non Finnish (NFE) AF: 0.00997 AC: 3929 AN: 394214

Other (OTH) AF: 0.0130 AC: 372 AN: 28690

⚠️ 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: 0.0128 AC: 1590 AN: 124420 Hom.: 4 Cov.: 0 AF XY: 0.0121 AC XY: 720 AN XY: 59400

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

African (AFR) AF: 0.0277 AC: 931 AN: 33592

American (AMR) AF: 0.00778 AC: 98 AN: 12590

Ashkenazi Jewish (ASJ) AF: 0.00791 AC: 24 AN: 3034

East Asian (EAS) AF: 0.0112 AC: 45 AN: 4004

South Asian (SAS) AF: 0.0201 AC: 78 AN: 3882

European-Finnish (FIN) AF: 0.000889 AC: 5 AN: 5624

Middle Eastern (MID) AF: 0.0142 AC: 3 AN: 212

European-Non Finnish (NFE) AF: 0.00598 AC: 353 AN: 59002

Other (OTH) AF: 0.0143 AC: 24 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.

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs544674838; hg19: chr15-99192754;