15-98853465-T-C

Variant names:

• chr15-98853465-T-C
• rs2684777
• NM_000875.5:c.641-37860T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000875.5(IGF1R):​c.641-37860T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,132 control chromosomes in the GnomAD database, including 4,345 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4345 hom., cov: 33)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.484
• Publications: 14 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]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.641-37860T>C		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.641-37860T>C		intron	N/A	NP_001278787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.641-37860T>C		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.641-37860T>C		intron	N/A
	IGF1R	ENST00000649865.1		c.641-37860T>C		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33151 AN: 152014 Hom.: 4340 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.230

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.218 AC: 33172 AN: 152132 Hom.: 4345 Cov.: 33 AF XY: 0.226 AC XY: 16796 AN XY: 74354

African (AFR) AF: 0.111 AC: 4596 AN: 41516

American (AMR) AF: 0.309 AC: 4730 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3470

East Asian (EAS) AF: 0.454 AC: 2345 AN: 5166

South Asian (SAS) AF: 0.353 AC: 1703 AN: 4818

European-Finnish (FIN) AF: 0.285 AC: 3017 AN: 10576

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15314 AN: 67986

Other (OTH) AF: 0.230 AC: 484 AN: 2102

Alfa AF: 0.217 Hom.: 6587

Bravo AF: 0.212

Asia WGS AF: 0.301 AC: 1047 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2684777; hg19: chr15-99396694; COSMIC: COSV51269315;