Genetic Variant NM_000875.5:c.3297+58T>C (chr15-98935484-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000875.5(IGF1R):c.3297+58T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 978,858 control chromosomes in the GnomAD database, including 90,017 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 12561 hom., cov: 31)

Exomes 𝑓: 0.43 ( 77456 hom. )

Consequence

IGF1R
NM_000875.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.368

Publications

20 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 Gene-Disease associations (from GenCC):

growth delay due to insulin-like growth factor I resistance
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

IGF1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5 link	c.3297+58T>C		intron_variant	Intron 17 of 20	ENST00000650285.1	NP_000866.1	P08069

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGF1R	ENST00000650285.1 link	c.3297+58T>C	intron_variant	Intron 17 of 20		NM_000875.5	ENSP00000497069.1	P08069
IGF1R	ENST00000649865.1 link	c.3294+58T>C	intron_variant	Intron 17 of 20			ENSP00000496919.1	C9J5X1
IGF1R	ENST00000560972.1 link	n.*118T>C	downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61173

AN:

151912

Hom.:

12550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.333

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.419

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.454

Gnomad OTH

AF:

0.390

GnomAD4 exome

AF:

0.428

AC:

353792

AN:

826828

Hom.:

77456

AF XY:

0.424

AC XY:

182177

AN XY:

429796

show subpopulations

African (AFR)

AF:

0.331

AC:

6836

AN:

20634

American (AMR)

AF:

0.351

AC:

12306

AN:

35052

Ashkenazi Jewish (ASJ)

AF:

0.474

AC:

10264

AN:

21642

East Asian (EAS)

AF:

0.305

AC:

10120

AN:

33158

South Asian (SAS)

AF:

0.313

AC:

21232

AN:

67878

European-Finnish (FIN)

AF:

0.426

AC:

20870

AN:

49038

Middle Eastern (MID)

AF:

0.370

AC:

1717

AN:

4642

European-Non Finnish (NFE)

AF:

0.457

AC:

254126

AN:

555496

Other (OTH)

AF:

0.415

AC:

16321

AN:

39288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

12452

24903

37355

49806

62258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5164

10328

15492

20656

25820

<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:

0.403

AC:

61216

AN:

152030

Hom.:

12561

Cov.:

AF XY:

0.400

AC XY:

29710

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.334

AC:

13832

AN:

41458

American (AMR)

AF:

0.383

AC:

5855

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1615

AN:

3472

East Asian (EAS)

AF:

0.340

AC:

1753

AN:

5162

South Asian (SAS)

AF:

0.323

AC:

1553

AN:

4814

European-Finnish (FIN)

AF:

0.419

AC:

4429

AN:

10576

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.454

AC:

30843

AN:

67958

Other (OTH)

AF:

0.385

AC:

810

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1893

3786

5678

7571

9464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.411

Hom.:

6601

Bravo

AF:

0.398

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.3

(source)

DANN

Benign

0.69

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over