NM_000875.5:c.641-70184A>G

Variant names:

• chr15-98821141-A-G
• rs2684761
• NM_000875.5:c.641-70184A>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.641-70184A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 151,998 control chromosomes in the GnomAD database, including 17,788 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 0.47 (17788 hom., cov: 32)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.764
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 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.641-70184A>G		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.641-70184A>G		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.641-70184A>G		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.641-70184A>G		intron	N/A
	IGF1R	ENST00000649865.1		c.641-70184A>G		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72025 AN: 151880 Hom.: 17775 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.474 AC: 72070 AN: 151998 Hom.: 17788 Cov.: 32 AF XY: 0.480 AC XY: 35671 AN XY: 74268

African (AFR) AF: 0.347 AC: 14363 AN: 41446

American (AMR) AF: 0.526 AC: 8038 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1500 AN: 3472

East Asian (EAS) AF: 0.629 AC: 3244 AN: 5158

South Asian (SAS) AF: 0.452 AC: 2181 AN: 4820

European-Finnish (FIN) AF: 0.616 AC: 6500 AN: 10556

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34720 AN: 67964

Other (OTH) AF: 0.433 AC: 912 AN: 2104

Alfa AF: 0.494 Hom.: 81274

Bravo AF: 0.463

Asia WGS AF: 0.492 AC: 1713 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.2
DANN	Benign	0.39
PhyloP100		0.76
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: rs2684761; hg19: chr15-99364370;