rs4966036

Variant names:

• chr15-98886520-T-C
• rs4966036
• NM_000875.5:c.641-4805T>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.641-4805T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,104 control chromosomes in the GnomAD database, including 5,431 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 0.26 (5431 hom., cov: 32)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 13 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

ENSG00000259621 (HGNC:58474):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 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.641-4805T>C		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.641-4805T>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.641-4805T>C		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.641-4805T>C		intron	N/A
	IGF1R	ENST00000649865.1		c.641-4805T>C		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39226 AN: 151986 Hom.: 5416 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.258 AC: 39278 AN: 152104 Hom.: 5431 Cov.: 32 AF XY: 0.267 AC XY: 19834 AN XY: 74336

African (AFR) AF: 0.282 AC: 11698 AN: 41504

American (AMR) AF: 0.312 AC: 4768 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3464

East Asian (EAS) AF: 0.414 AC: 2137 AN: 5166

South Asian (SAS) AF: 0.283 AC: 1364 AN: 4816

European-Finnish (FIN) AF: 0.330 AC: 3485 AN: 10562

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14566 AN: 67994

Other (OTH) AF: 0.251 AC: 531 AN: 2112

Alfa AF: 0.226 Hom.: 2399

Bravo AF: 0.257

Asia WGS AF: 0.282 AC: 980 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.84
DANN	Benign	0.43
PhyloP100		-0.054
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: rs4966036; hg19: chr15-99429749;