Genetic Variant IGF1R:c.-38_-33dupTTTTTT (chr15-98649525-C-CTTTTTT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000875.5(IGF1R):c.-38_-33dupTTTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00051 ( 2 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.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.-38_-33dupTTTTTT	5_prime_UTR	Exon 1 of 21	NP_000866.1	P08069
IGF1R	NM_001291858.2		c.-38_-33dupTTTTTT	5_prime_UTR	Exon 1 of 21	NP_001278787.1	C9J5X1
IRAIN	NR_126453.2		n.1257_1262dupAAAAAA	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.-38_-33dupTTTTTT	5_prime_UTR	Exon 1 of 21	ENSP00000497069.1	P08069
IGF1R	ENST00000649865.1		c.-38_-33dupTTTTTT	5_prime_UTR	Exon 1 of 21	ENSP00000496919.1	C9J5X1
ENSG00000278022	ENST00000747447.1		n.83+2313_83+2318dupTTTTTT	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000393

AC:

AN:

124628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000890

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000159

Gnomad ASJ

AF:

0.000330

Gnomad EAS

AF:

0.00124

Gnomad SAS

AF:

0.000765

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000593

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000505

AC:

304

AN:

601468

Hom.:

Cov.:

AF XY:

0.000486

AC XY:

156

AN XY:

320966

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

13900

American (AMR)

AF:

0.000653

AC:

AN:

24490

Ashkenazi Jewish (ASJ)

AF:

0.000674

AC:

AN:

16322

East Asian (EAS)

AF:

0.000145

AC:

AN:

27554

South Asian (SAS)

AF:

0.00153

AC:

AN:

52272

European-Finnish (FIN)

AF:

0.000357

AC:

AN:

36384

Middle Eastern (MID)

AF:

0.000675

AC:

AN:

2964

European-Non Finnish (NFE)

AF:

0.000412

AC:

164

AN:

398526

Other (OTH)

AF:

0.000379

AC:

AN:

29056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000393

AC:

AN:

124628

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

59490

show subpopulations

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

African (AFR)

AF:

0.0000890

AC:

AN:

33690

American (AMR)

AF:

0.000159

AC:

AN:

12598

Ashkenazi Jewish (ASJ)

AF:

0.000330

AC:

AN:

3032

East Asian (EAS)

AF:

0.00124

AC:

AN:

4022

South Asian (SAS)

AF:

0.000765

AC:

AN:

3920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.000593

AC:

AN:

59046

Other (OTH)

AF:

0.00

AC:

AN:

1672

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

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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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