15-98916049-C-T

Position:

chr15-98916049-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000875.5(IGF1R):c.1914C>T(p.Asn638=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00948 in 1,614,182 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0097 ( 101 hom. )

Consequence

IGF1R
NM_000875.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0460

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 15-98916049-C-T is Benign according to our data. Variant chr15-98916049-C-T is described in ClinVar as [Benign]. Clinvar id is 199042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98916049-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.046 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0075 (1142/152348) while in subpopulation NFE AF= 0.0108 (737/68030). AF 95% confidence interval is 0.0102. There are 7 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5 linkuse as main transcript	c.1914C>T	p.Asn638=	synonymous_variant	9/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
IGF1R	ENST00000650285.1 linkuse as main transcript	c.1914C>T	p.Asn638=	synonymous_variant	9/21		NM_000875.5	ENSP00000497069	P4
IGF1R	ENST00000559925.5 linkuse as main transcript	n.1914C>T		non_coding_transcript_exon_variant	9/10	1
IGF1R	ENST00000649865.1 linkuse as main transcript	c.1914C>T	p.Asn638=	synonymous_variant	9/21			ENSP00000496919	A1
IGF1R	ENST00000560144.1 linkuse as main transcript	c.145C>T	p.Arg49Trp	missense_variant, NMD_transcript_variant	2/4	3		ENSP00000456950

Frequencies

GnomAD3 genomes

AF:

0.00750

AC:

1142

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00776

AC:

1952

AN:

251484

Hom.:

AF XY:

0.00767

AC XY:

1042

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0143

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00968

AC:

14153

AN:

1461834

Hom.:

101

Cov.:

AF XY:

0.00951

AC XY:

6914

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.00814

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000707

Gnomad4 FIN exome

AF:

0.0131

Gnomad4 NFE exome

AF:

0.0109

Gnomad4 OTH exome

AF:

0.00944

GnomAD4 genome

AF:

0.00750

AC:

1142

AN:

152348

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

539

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00895

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.0108

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00919

Hom.:

Bravo

AF:

0.00736

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	IGF1R: BP4, BP7, BS1, BS2 -
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)

Mar 17, 2015

- -

Growth delay due to insulin-like growth factor I resistance

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

7.0

DANN

Uncertain

0.99

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