15-98957376-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000875.5(IGF1R):c.4038C>T(p.Tyr1346Tyr) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.628

Variant links:

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 links:

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

SYNM-AS1 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
IGF1R	NM_000875.5 link	c.4038C>T	p.Tyr1346Tyr	synonymous_variant	Exon 21 of 21	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGF1R	ENST00000650285.1 link	c.4038C>T	p.Tyr1346Tyr	synonymous_variant	Exon 21 of 21		NM_000875.5	ENSP00000497069.1	P08069
IGF1R	ENST00000649865.1 link	c.4035C>T	p.Tyr1345Tyr	synonymous_variant	Exon 21 of 21			ENSP00000496919.1	C9J5X1
SYNM-AS1	ENST00000559468.1 link	n.349-2988G>A		intron_variant	Intron 3 of 3	4
IGF1R	ENST00000558751.1 link	n.*84C>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0681

AC:

10372

AN:

152206

Hom.:

485

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0491

AC XY:

35706

AN XY:

726808

show subpopulations

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.:

AF XY:

0.0681

AC XY:

5072

AN XY:

74478

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Apr 06, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Growth delay due to insulin-like growth factor I resistance

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over