rs4966035

Variant names:

• chr15-98886233-G-A
• rs4966035
• NM_000875.5:c.641-5092G>A

Variant summary

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

The NM_000875.5(IGF1R):​c.641-5092G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 151,930 control chromosomes in the GnomAD database, including 10,012 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 0.36 (10012 hom., cov: 32)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.422
• Publications: 20 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.641-5092G>A		intron_variant	Intron 2 of 20	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.641-5092G>A		intron_variant	Intron 2 of 20		NM_000875.5	ENSP00000497069.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54175 AN: 151812 Hom.: 9998 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.357 AC: 54236 AN: 151930 Hom.: 10012 Cov.: 32 AF XY: 0.368 AC XY: 27303 AN XY: 74228

African (AFR) AF: 0.370 AC: 15349 AN: 41440

American (AMR) AF: 0.430 AC: 6565 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3468

East Asian (EAS) AF: 0.562 AC: 2900 AN: 5158

South Asian (SAS) AF: 0.396 AC: 1909 AN: 4824

European-Finnish (FIN) AF: 0.419 AC: 4392 AN: 10490

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21285 AN: 67962

Other (OTH) AF: 0.353 AC: 745 AN: 2110

Alfa AF: 0.323 Hom.: 28449

Bravo AF: 0.357

Asia WGS AF: 0.417 AC: 1447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.45
PhyloP100		0.42
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: rs4966035; hg19: chr15-99429462;