rs2229765

Positions:

• chr15-98934996-G-A
• chr15-98934996-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000875.5(IGF1R):​c.3129G>A​(p.Glu1043=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,534 control chromosomes in the GnomAD database, including 151,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11963 hom., cov: 31)
  • Exomes 𝑓: 0.43 (139575 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.148

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-98934996-G-A is Benign according to our data. Variant chr15-98934996-G-A is described in ClinVar as [Benign]. Clinvar id is 194610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98934996-G-A is described in Lovd as [Likely_benign]. Variant chr15-98934996-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.148 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3129G>A	p.Glu1043=	synonymous_variant	16/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3129G>A	p.Glu1043=	synonymous_variant	16/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000560972.1	n.260-320G>A		intron_variant, non_coding_transcript_variant		1
IGF1R	ENST00000649865.1	c.3126G>A	p.Glu1042=	synonymous_variant	16/21			ENSP00000496919	A1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59377 AN: 151908 Hom.: 11959 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.384

GnomAD3 exomes AF: 0.397 AC: 99711 AN: 251348 Hom.: 20615 AF XY: 0.398 AC XY: 54082 AN XY: 135832

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.351

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.433 AC: 632746 AN: 1461508 Hom.: 139575 Cov.: 46 AF XY: 0.430 AC XY: 312426 AN XY: 727054

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.343

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.311

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.422

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.391 AC: 59409 AN: 152026 Hom.: 11963 Cov.: 31 AF XY: 0.388 AC XY: 28824 AN XY: 74304

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.413

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.379

Alfa AF: 0.429 Hom.: 12965

Bravo AF: 0.385

Asia WGS AF: 0.322 AC: 1120 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.438

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 17, 2014

- -

Growth delay due to insulin-like growth factor I resistance Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.2
DANN	Benign	0.50

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: rs2229765; hg19: chr15-99478225; COSMIC: COSV51291816;