Genetic Variant IGF1R:c.-43_-33dupTTTTTTTTTTT (chr15-98649525-C-CTTTTTTTTTTT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_000875.5(IGF1R):c.-43_-33dupTTTTTTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

IGF1R
NM_000875.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.295

Publications

2 publications found

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:

IRAIN (HGNC:50365): (IGF1R antisense imprinted non-protein coding RNA) This gene expresses a long non-coding RNA in antisense to the insulin-like growth factor type I receptor (IGF1R) gene. This transcript is imprinted and expressed from the paternal allele. It interacts with chromatin and may promote long-range DNA interactions that influence the regulation of gene expression. [provided by RefSeq, Nov 2015]

IRAIN links:

ENSG00000278022 (HGNC:):

ENSG00000278022 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00019 (114/601552) while in subpopulation SAS AF = 0.000689 (36/52282). AF 95% confidence interval is 0.000511. There are 1 homozygotes in GnomAdExome4. There are 65 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGF1R	NM_000875.5	MANE Select	c.-43_-33dupTTTTTTTTTTT	5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
IGF1R	NM_001291858.2		c.-43_-33dupTTTTTTTTTTT	5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
IRAIN	NR_126453.2		n.1252_1262dupAAAAAAAAAAA	non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGF1R	ENST00000650285.1	MANE Select	c.-43_-33dupTTTTTTTTTTT	5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
IGF1R	ENST00000649865.1		c.-43_-33dupTTTTTTTTTTT	5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
ENSG00000278022	ENST00000747447.1		n.83+2308_83+2318dupTTTTTTTTTTT	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000562

AC:

AN:

124650

Hom.:

Cov.:

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:

0.000249

Gnomad SAS

AF:

0.000255

Gnomad FIN

AF:

0.000178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000677

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

114

AN:

601552

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

321010

show subpopulations

African (AFR)

AF:

0.0000719

AC:

AN:

13902

American (AMR)

AF:

0.000367

AC:

AN:

24498

Ashkenazi Jewish (ASJ)

AF:

0.000368

AC:

AN:

16324

East Asian (EAS)

AF:

0.000145

AC:

AN:

27560

South Asian (SAS)

AF:

0.000689

AC:

AN:

52282

European-Finnish (FIN)

AF:

0.0000550

AC:

AN:

36386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2964

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

398572

Other (OTH)

AF:

0.000103

AC:

AN:

29064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000562

AC:

AN:

124658

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

59522

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33738

American (AMR)

AF:

0.00

AC:

AN:

12608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3036

East Asian (EAS)

AF:

0.000249

AC:

AN:

4012

South Asian (SAS)

AF:

0.000257

AC:

AN:

3896

European-Finnish (FIN)

AF:

0.000178

AC:

AN:

5624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000677

AC:

AN:

59052

Other (OTH)

AF:

0.00

AC:

AN:

1684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000686732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.296

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.29

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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15-98649525-CTTTTTTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over