15-98948832-G-A

Variant names:

• chr15-98948832-G-A
• rs17847195
• NM_000875.5:c.3722+124G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000875.5(IGF1R):​c.3722+124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,154,382 control chromosomes in the GnomAD database, including 30,273 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 0.18 (2820 hom., cov: 33)
  • Exomes 𝑓: 0.23 (27453 hom.)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 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.3722+124G>A		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.3719+124G>A		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.3722+124G>A		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000649865.1		c.3719+124G>A		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27509 AN: 152122 Hom.: 2820 Cov.: 33

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.229 AC: 229520 AN: 1002142 Hom.: 27453 AF XY: 0.234 AC XY: 121213 AN XY: 517654

African (AFR) AF: 0.0746 AC: 1858 AN: 24898

American (AMR) AF: 0.167 AC: 7207 AN: 43122

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 5778 AN: 23212

East Asian (EAS) AF: 0.308 AC: 11543 AN: 37516

South Asian (SAS) AF: 0.326 AC: 24915 AN: 76398

European-Finnish (FIN) AF: 0.206 AC: 8062 AN: 39046

Middle Eastern (MID) AF: 0.235 AC: 1100 AN: 4674

European-Non Finnish (NFE) AF: 0.224 AC: 158713 AN: 707544

Other (OTH) AF: 0.226 AC: 10344 AN: 45732

GnomAD4 genome AF: 0.181 AC: 27505 AN: 152240 Hom.: 2820 Cov.: 33 AF XY: 0.183 AC XY: 13621 AN XY: 74444

African (AFR) AF: 0.0766 AC: 3184 AN: 41542

American (AMR) AF: 0.169 AC: 2577 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3470

East Asian (EAS) AF: 0.263 AC: 1363 AN: 5178

South Asian (SAS) AF: 0.332 AC: 1604 AN: 4828

European-Finnish (FIN) AF: 0.213 AC: 2255 AN: 10604

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15035 AN: 68012

Other (OTH) AF: 0.185 AC: 391 AN: 2114

Alfa AF: 0.0970 Hom.: 153

Bravo AF: 0.171

Asia WGS AF: 0.239 AC: 830 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.56
PhyloP100		0.69
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: rs17847195; hg19: chr15-99492061; COSMIC: COSV51309204; COSMIC: COSV51309204;