rs3743259

Variant names:

• chr15-98899932-A-G
• rs3743259
• NM_000875.5:c.1247+311A>G

Variant summary

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

The NM_000875.5(IGF1R):​c.1247+311A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,018 control chromosomes in the GnomAD database, including 10,021 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 0.35 (10021 hom., cov: 33)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 12 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

ENSG00000304780 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.1247+311A>G		intron_variant	Intron 5 of 20	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.1247+311A>G		intron_variant	Intron 5 of 20		NM_000875.5	ENSP00000497069.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53710 AN: 151900 Hom.: 10007 Cov.: 33

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.354 AC: 53772 AN: 152018 Hom.: 10021 Cov.: 33 AF XY: 0.365 AC XY: 27119 AN XY: 74306

African (AFR) AF: 0.397 AC: 16427 AN: 41430

American (AMR) AF: 0.425 AC: 6500 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 710 AN: 3470

East Asian (EAS) AF: 0.556 AC: 2867 AN: 5160

South Asian (SAS) AF: 0.381 AC: 1835 AN: 4822

European-Finnish (FIN) AF: 0.407 AC: 4300 AN: 10566

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 19990 AN: 67972

Other (OTH) AF: 0.354 AC: 747 AN: 2110

Alfa AF: 0.310 Hom.: 3860

Bravo AF: 0.358

Asia WGS AF: 0.406 AC: 1410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.9
DANN	Benign	0.38
PhyloP100		-0.066
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: rs3743259; hg19: chr15-99443161;