15-98903403-G-C

Variant names:

• chr15-98903403-G-C
• rs4966038
• NM_000875.5:c.1247+3782G>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.1247+3782G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,164 control chromosomes in the GnomAD database, including 6,869 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 0.29 (6869 hom., cov: 32)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.444
• Publications: 7 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.1247+3782G>C		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+3782G>C		intron_variant	Intron 5 of 20		NM_000875.5	ENSP00000497069.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43714 AN: 152046 Hom.: 6858 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.293

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

GnomAD4 genome AF: 0.288 AC: 43761 AN: 152164 Hom.: 6869 Cov.: 32 AF XY: 0.298 AC XY: 22177 AN XY: 74400

African (AFR) AF: 0.176 AC: 7313 AN: 41532

American (AMR) AF: 0.347 AC: 5305 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 699 AN: 3466

East Asian (EAS) AF: 0.425 AC: 2204 AN: 5180

South Asian (SAS) AF: 0.339 AC: 1635 AN: 4826

European-Finnish (FIN) AF: 0.426 AC: 4506 AN: 10572

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21097 AN: 67984

Other (OTH) AF: 0.291 AC: 614 AN: 2110

Alfa AF: 0.302 Hom.: 903

Bravo AF: 0.277

Asia WGS AF: 0.309 AC: 1072 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.21
PhyloP100		0.44
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: rs4966038; hg19: chr15-99446632;