15-98935484-T-G

Variant names:

• chr15-98935484-T-G
• rs2293117
• NM_000875.5:c.3297+58T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000875.5(IGF1R):​c.3297+58T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 980,248 control chromosomes in the GnomAD database, including 13 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 0.00038 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00071 (12 hom.)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 20 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=-0.93).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000381 (58/152096) while in subpopulation SAS AF = 0.0114 (55/4818). AF 95% confidence interval is 0.00901. There are 1 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR,AD gene

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.3297+58T>G		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.3294+58T>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.3297+58T>G		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000649865.1		c.3294+58T>G		intron	N/A	ENSP00000496919.1
	IGF1R	ENST00000560972.1	TSL:1	n.*118T>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 151978 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000705 AC: 584 AN: 828152 Hom.: 12 AF XY: 0.000999 AC XY: 430 AN XY: 430394

African (AFR) AF: 0.00 AC: 0 AN: 20656

American (AMR) AF: 0.00 AC: 0 AN: 35054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21652

East Asian (EAS) AF: 0.0000301 AC: 1 AN: 33170

South Asian (SAS) AF: 0.00819 AC: 556 AN: 67908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49050

Middle Eastern (MID) AF: 0.000215 AC: 1 AN: 4644

European-Non Finnish (NFE) AF: 0.00000539 AC: 3 AN: 556694

Other (OTH) AF: 0.000585 AC: 23 AN: 39324

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152096 Hom.: 1 Cov.: 31 AF XY: 0.000551 AC XY: 41 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41484

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00 Hom.: 6601

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.6
DANN	Benign	0.72
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

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: rs2293117; hg19: chr15-99478713;