15-98957376-C-T

Variant names:

• chr15-98957376-C-T
• rs17847203
• NM_000875.5:c.4038C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.628
• Publications: 15 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]

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 287436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.4038C>T	p.Tyr1346Tyr	synonymous_variant	Exon 21 of 21	ENST00000650285.1	NP_000866.1

Ensembl

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

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

GnomAD2 exomes AF: 0.0593 AC: 14784 AN: 249380 AF XY: 0.0561

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 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

African (AFR) AF: 0.123 AC: 4125 AN: 33480

American (AMR) AF: 0.110 AC: 4921 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 633 AN: 26132

East Asian (EAS) AF: 0.0298 AC: 1183 AN: 39698

South Asian (SAS) AF: 0.0711 AC: 6129 AN: 86252

European-Finnish (FIN) AF: 0.0353 AC: 1858 AN: 52640

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5760

European-Non Finnish (NFE) AF: 0.0445 AC: 49490 AN: 1111934

Other (OTH) AF: 0.0466 AC: 2812 AN: 60382

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

African (AFR) AF: 0.118 AC: 4893 AN: 41566

American (AMR) AF: 0.0858 AC: 1313 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.0344 AC: 178 AN: 5174

South Asian (SAS) AF: 0.0636 AC: 307 AN: 4828

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10624

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0441 AC: 2999 AN: 68028

Other (OTH) AF: 0.0468 AC: 99 AN: 2116

Alfa AF: 0.0550 Hom.: 181

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

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.63
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: rs17847203; hg19: chr15-99500605; COSMIC: COSV51294127;