chr15-98649689-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000875.5(IGF1R):​c.94+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,593,810 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 20 hom., cov: 32)
Exomes 𝑓: 0.00088 ( 11 hom. )

Consequence

IGF1R
NM_000875.5 intron

Scores

1
1

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.681
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 Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.34).
BP6
Variant 15-98649689-C-T is Benign according to our data. Variant chr15-98649689-C-T is described in ClinVar as [Benign]. Clinvar id is 317439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98649689-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00968 (1473/152142) while in subpopulation AFR AF= 0.0337 (1399/41536). AF 95% confidence interval is 0.0322. There are 20 homozygotes in gnomad4. There are 723 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IGF1RNM_000875.5 linkuse as main transcriptc.94+14C>T intron_variant ENST00000650285.1
IRAINNR_126453.2 linkuse as main transcriptn.1099G>A 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+14C>T intron_variant NM_000875.5 P4
IGF1RENST00000559925.5 linkuse as main transcriptn.94+14C>T intron_variant, non_coding_transcript_variant 1
IGF1RENST00000649865.1 linkuse as main transcriptc.94+14C>T intron_variant A1

Frequencies

GnomAD3 genomes
AF:
0.00967
AC:
1470
AN:
152036
Hom.:
20
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0337
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00353
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00231
AC:
568
AN:
245420
Hom.:
10
AF XY:
0.00187
AC XY:
249
AN XY:
133496
show subpopulations
Gnomad AFR exome
AF:
0.0329
Gnomad AMR exome
AF:
0.00135
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000333
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000450
Gnomad OTH exome
AF:
0.000506
GnomAD4 exome
AF:
0.000875
AC:
1262
AN:
1441668
Hom.:
11
Cov.:
28
AF XY:
0.000777
AC XY:
558
AN XY:
718222
show subpopulations
Gnomad4 AFR exome
AF:
0.0315
Gnomad4 AMR exome
AF:
0.00156
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000234
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000912
Gnomad4 OTH exome
AF:
0.00235
GnomAD4 genome
AF:
0.00968
AC:
1473
AN:
152142
Hom.:
20
Cov.:
32
AF XY:
0.00972
AC XY:
723
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.0337
Gnomad4 AMR
AF:
0.00353
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00507
Hom.:
4
Bravo
AF:
0.0108
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Growth delay due to insulin-like growth factor I resistance Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.34
CADD
Benign
19
DANN
Uncertain
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs35275105; hg19: chr15-99192918; COSMIC: COSV51273197; COSMIC: COSV51273197; API