15-98939699-A-G

Variant names:

• chr15-98939699-A-G
• rs8038056
• NM_000875.5:c.3457+339A>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.3457+339A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,188 control chromosomes in the GnomAD database, including 1,558 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 0.13 (1558 hom., cov: 33)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541
• Publications: 9 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 = 0.331 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.3457+339A>G		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.3454+339A>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.3457+339A>G		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000649865.1		c.3454+339A>G		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19242 AN: 152070 Hom.: 1541 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.0469

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0875

Gnomad OTH AF: 0.152

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

GnomAD4 genome AF: 0.127 AC: 19285 AN: 152188 Hom.: 1558 Cov.: 33 AF XY: 0.133 AC XY: 9919 AN XY: 74422

African (AFR) AF: 0.119 AC: 4943 AN: 41494

American (AMR) AF: 0.252 AC: 3850 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 163 AN: 3472

East Asian (EAS) AF: 0.344 AC: 1777 AN: 5168

South Asian (SAS) AF: 0.141 AC: 679 AN: 4830

European-Finnish (FIN) AF: 0.142 AC: 1506 AN: 10600

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0875 AC: 5950 AN: 68008

Other (OTH) AF: 0.161 AC: 341 AN: 2114

Alfa AF: 0.101 Hom.: 4242

Bravo AF: 0.137

Asia WGS AF: 0.286 AC: 995 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	6.7
DANN	Benign	0.78
PhyloP100		0.54
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: rs8038056; hg19: chr15-99482928;