Genetic Variant IGF1R:c.*3129G>T (chr15-98960571-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000875.5(IGF1R):c.*3129G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 233,420 control chromosomes in the GnomAD database, including 27,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16545 hom., cov: 33)

Exomes 𝑓: 0.52 ( 10908 hom. )

Consequence

IGF1R
NM_000875.5 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.529

Publications

38 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:

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

SYNM-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 15-98960571-G-T is Benign according to our data. Variant chr15-98960571-G-T is described in ClinVar as Benign. ClinVar VariationId is 317546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.*3129G>T		3_prime_UTR	Exon 21 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.*3129G>T		3_prime_UTR	Exon 21 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGF1R	ENST00000650285.1	MANE Select	c.*3129G>T	3_prime_UTR	Exon 21 of 21	ENSP00000497069.1	P08069
IGF1R	ENST00000649865.1		c.*3129G>T	3_prime_UTR	Exon 21 of 21	ENSP00000496919.1	C9J5X1
SYNM-AS1	ENST00000559468.1	TSL:4	n.348+5418C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.458

AC:

69631

AN:

151992

Hom.:

16535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.324

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.455

Gnomad ASJ

AF:

0.521

Gnomad EAS

AF:

0.526

Gnomad SAS

AF:

0.610

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.512

Gnomad OTH

AF:

0.483

GnomAD4 exome

AF:

0.515

AC:

41907

AN:

81310

Hom.:

10908

Cov.:

AF XY:

0.518

AC XY:

19416

AN XY:

37478

show subpopulations

African (AFR)

AF:

0.329

AC:

1283

AN:

3904

American (AMR)

AF:

0.457

AC:

1141

AN:

2498

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

2673

AN:

5126

East Asian (EAS)

AF:

0.579

AC:

6612

AN:

11418

South Asian (SAS)

AF:

0.630

AC:

447

AN:

710

European-Finnish (FIN)

AF:

0.544

AC:

AN:

Middle Eastern (MID)

AF:

0.520

AC:

257

AN:

494

European-Non Finnish (NFE)

AF:

0.518

AC:

26044

AN:

50304

Other (OTH)

AF:

0.503

AC:

3413

AN:

6788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1198

2395

3593

4790

5988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.458

AC:

69678

AN:

152110

Hom.:

16545

Cov.:

AF XY:

0.461

AC XY:

34277

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.324

AC:

13473

AN:

41528

American (AMR)

AF:

0.455

AC:

6952

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

1807

AN:

3470

East Asian (EAS)

AF:

0.526

AC:

2708

AN:

5144

South Asian (SAS)

AF:

0.610

AC:

2938

AN:

4816

European-Finnish (FIN)

AF:

0.528

AC:

5588

AN:

10582

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.512

AC:

34788

AN:

67968

Other (OTH)

AF:

0.486

AC:

1026

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1922

3845

5767

7690

9612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.487

Hom.:

35315

Bravo

AF:

0.444

Asia WGS

AF:

0.540

AC:

1875

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Growth delay due to insulin-like growth factor I resistance (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.5

(source)

DANN

Benign

0.61

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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