chr15-98649674-AAGTG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPP3_Moderate

The NM_000875.5(IGF1R):​c.94+3_94+6del variant causes a splice donor, splice donor region, coding sequence, intron change. The variant allele was found at a frequency of 0.0000162 in 1,607,578 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

IGF1R
NM_000875.5 splice_donor, splice_donor_region, coding_sequence, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.72
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2768031 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 0 (no position change), new splice context is: aaaGTatgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IGF1RNM_000875.5 linkuse as main transcriptc.94+3_94+6del splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant 1/21 ENST00000650285.1
IRAINNR_126453.2 linkuse as main transcriptn.1110_1113del non_coding_transcript_exon_variant 1/1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IGF1RENST00000650285.1 linkuse as main transcriptc.94+3_94+6del splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant 1/21 NM_000875.5 P4
IGF1RENST00000559925.5 linkuse as main transcriptn.94+3_94+6del splice_donor_variant, splice_donor_region_variant, non_coding_transcript_exon_variant, intron_variant 1/101
IGF1RENST00000649865.1 linkuse as main transcriptc.94+3_94+6del splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant 1/21 A1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151818
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000951
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000364
AC:
9
AN:
247466
Hom.:
0
AF XY:
0.0000298
AC XY:
4
AN XY:
134388
show subpopulations
Gnomad AFR exome
AF:
0.0000629
Gnomad AMR exome
AF:
0.0000297
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000551
Gnomad SAS exome
AF:
0.0000994
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000172
AC:
25
AN:
1455760
Hom.:
0
AF XY:
0.0000166
AC XY:
12
AN XY:
724478
show subpopulations
Gnomad4 AFR exome
AF:
0.0000601
Gnomad4 AMR exome
AF:
0.000113
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.0000382
Gnomad4 NFE exome
AF:
0.00000902
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151818
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74144
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000951
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 15, 2023This sequence change falls in intron 1 of the IGF1R gene. It does not directly change the encoded amino acid sequence of the IGF1R protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs779160550, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IGF1R-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.96
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.40
Position offset: 5
DS_DL_spliceai
0.96
Position offset: 1

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.

Other links and lift over

dbSNP: rs779160550; hg19: chr15-99192903; API