rs2684774

Variant names:

• chr15-98836794-T-G
• rs2684774
• NM_000875.5:c.641-54531T>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.641-54531T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,160 control chromosomes in the GnomAD database, including 4,361 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 0.20 (4361 hom., cov: 32)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643
• Publications: 2 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

LOC124903561 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.641-54531T>G		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.641-54531T>G		intron_variant	Intron 2 of 20		NM_000875.5	ENSP00000497069.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30992 AN: 152040 Hom.: 4322 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.204 AC: 31084 AN: 152160 Hom.: 4361 Cov.: 32 AF XY: 0.203 AC XY: 15120 AN XY: 74402

African (AFR) AF: 0.397 AC: 16475 AN: 41468

American (AMR) AF: 0.135 AC: 2058 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3472

East Asian (EAS) AF: 0.148 AC: 764 AN: 5170

South Asian (SAS) AF: 0.179 AC: 865 AN: 4826

European-Finnish (FIN) AF: 0.0993 AC: 1054 AN: 10614

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8607 AN: 68000

Other (OTH) AF: 0.210 AC: 444 AN: 2112

Alfa AF: 0.174 Hom.: 391

Bravo AF: 0.214

Asia WGS AF: 0.186 AC: 647 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.3
DANN	Benign	0.81
PhyloP100		0.64
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: rs2684774; hg19: chr15-99380023;