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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000875.5(IGF1R):c.3297+58T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 980,248 control chromosomes in the GnomAD database, including 13 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 0.00038 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00071 ( 12 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=-0.93).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000381 (58/152096) while in subpopulation SAS AF = 0.0114 (55/4818). AF 95% confidence interval is 0.00901. There are 1 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR,AD gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.000382

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000705

AC:

584

AN:

828152

Hom.:

AF XY:

0.000999

AC XY:

430

AN XY:

430394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20656

American (AMR)

AF:

0.00

AC:

AN:

35054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21652

East Asian (EAS)

AF:

0.0000301

AC:

AN:

33170

South Asian (SAS)

AF:

0.00819

AC:

556

AN:

67908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49050

Middle Eastern (MID)

AF:

0.000215

AC:

AN:

4644

European-Non Finnish (NFE)

AF:

0.00000539

AC:

AN:

556694

Other (OTH)

AF:

0.000585

AC:

AN:

39324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000381

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41484

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0114

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

6601

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

3.6

(source)

DANN

Benign

0.72

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism

(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