rs4966015

Variant names:

• chr15-98704903-G-T
• rs4966015
• NM_000875.5:c.95-2659G>T

Variant summary

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

The NM_000875.5(IGF1R):​c.95-2659G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,046 control chromosomes in the GnomAD database, including 2,666 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 0.18 (2666 hom., cov: 31)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.499
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.236 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.95-2659G>T		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.95-2659G>T		intron	N/A	NP_001278787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.95-2659G>T		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.95-2659G>T		intron	N/A
	IGF1R	ENST00000649865.1		c.95-2659G>T		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27373 AN: 151928 Hom.: 2666 Cov.: 31

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.180 AC: 27373 AN: 152046 Hom.: 2666 Cov.: 31 AF XY: 0.184 AC XY: 13668 AN XY: 74322

African (AFR) AF: 0.221 AC: 9179 AN: 41446

American (AMR) AF: 0.212 AC: 3232 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 409 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1045 AN: 5152

South Asian (SAS) AF: 0.248 AC: 1195 AN: 4822

European-Finnish (FIN) AF: 0.197 AC: 2088 AN: 10596

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.140 AC: 9543 AN: 67988

Other (OTH) AF: 0.184 AC: 388 AN: 2110

Alfa AF: 0.156 Hom.: 2804

Bravo AF: 0.182

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.36
DANN	Benign	0.41
PhyloP100		-0.50
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: rs4966015; hg19: chr15-99248132;