rs55770488

chr15-98707692-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000875.5(IGF1R):c.225C>T(p.Phe75=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,178 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (13 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.733

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-98707692-C-T is Benign according to our data. Variant chr15-98707692-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 281171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98707692-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.733 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00298 (454/152286) while in subpopulation NFE AF= 0.00494 (336/68020). AF 95% confidence interval is 0.0045. There are 4 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.225C>T	p.Phe75=	synonymous_variant	2/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.225C>T	p.Phe75=	synonymous_variant	2/21		NM_000875.5	P4
IGF1R	ENST00000559925.5	n.225C>T		non_coding_transcript_exon_variant	2/10	1
IGF1R	ENST00000649865.1	c.225C>T	p.Phe75=	synonymous_variant	2/21			A1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00278 AC: 699 AN: 251452 Hom.: 1 AF XY: 0.00279 AC XY: 379 AN XY: 135902

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00456

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00378 AC: 5532 AN: 1461892 Hom.: 13 Cov.: 33 AF XY: 0.00375 AC XY: 2728 AN XY: 727246

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152286 Hom.: 4 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74458

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00494

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00295

EpiCase AF: 0.00365

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 11, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	IGF1R: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 13, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.1
Dann	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs55770488; hg19: chr15-99250921; COSMIC: COSV51406540; COSMIC: COSV51406540;