15-98957376-C-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.4038C>T(p.Tyr1346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,613,316 control chromosomes in the GnomAD database, including 2,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (487 hom., cov: 33)
  • Exomes 𝑓: 0.049 (2145 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.628

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]

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-98957376-C-T is Benign according to our data. Variant chr15-98957376-C-T is described in ClinVar as [Benign]. Clinvar id is 287436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98957376-C-T is described in Lovd as [Likely_benign]. Variant chr15-98957376-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.628 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.4038C>T	p.Tyr1346=	synonymous_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.4038C>T	p.Tyr1346=	synonymous_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.349-2988G>A		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.4035C>T	p.Tyr1345=	synonymous_variant	21/21			A1

Frequencies

GnomAD3 genomes AF: 0.0681 AC: 10372 AN: 152206 Hom.: 485 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0345

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0441

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0593 AC: 14784 AN: 249380 Hom.: 594 AF XY: 0.0561 AC XY: 7597 AN XY: 135316

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.0341

Gnomad SAS exome AF: 0.0708

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0530

GnomAD4 exome AF: 0.0488 AC: 71363 AN: 1460992 Hom.: 2145 Cov.: 34 AF XY: 0.0491 AC XY: 35706 AN XY: 726808

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.0298

Gnomad4 SAS exome AF: 0.0711

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0466

GnomAD4 genome AF: 0.0682 AC: 10385 AN: 152324 Hom.: 487 Cov.: 33 AF XY: 0.0681 AC XY: 5072 AN XY: 74478

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0858

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.0344

Gnomad4 SAS AF: 0.0636

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0441

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0552 Hom.: 137

Bravo AF: 0.0740

Asia WGS AF: 0.0610 AC: 211 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 06, 2016

- -

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

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

IGF1R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	5.6
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: rs17847203; hg19: chr15-99500605; COSMIC: COSV51294127; COSMIC: COSV51294127;