Genetic Variant IGFBP3:c.751-485T>C (chr7-45915430-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000598.5(IGFBP3):c.751-485T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 166,420 control chromosomes in the GnomAD database, including 27,750 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 0.58 ( 25507 hom., cov: 32)

Exomes 𝑓: 0.55 ( 2243 hom. )

Consequence

IGFBP3
NM_000598.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.199

Publications

69 publications found

Variant links:

Genes affected

IGFBP3 (HGNC:5472): (insulin like growth factor binding protein 3) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein forms a ternary complex with insulin-like growth factor acid-labile subunit (IGFALS) and either insulin-like growth factor (IGF) I or II. In this form, it circulates in the plasma, prolonging the half-life of IGFs and altering their interaction with cell surface receptors. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

IGFBP3 links:

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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=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000598.5. 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
	IGFBP3	NM_000598.5	MANE Select	c.751-485T>C		intron	N/A	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.769-485T>C		intron	N/A	NP_001013416.1	P17936-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGFBP3	ENST00000613132.5	TSL:5 MANE Select	c.751-485T>C	intron	N/A	ENSP00000477772.2	P17936-1
IGFBP3	ENST00000908406.1		c.841-485T>C	intron	N/A	ENSP00000578465.1
IGFBP3	ENST00000381083.9	TSL:5	c.769-485T>C	intron	N/A	ENSP00000370473.4	P17936-2

Frequencies

GnomAD3 genomes

AF:

0.576

AC:

87525

AN:

151924

Hom.:

25503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.622

Gnomad AMI

AF:

0.678

Gnomad AMR

AF:

0.442

Gnomad ASJ

AF:

0.633

Gnomad EAS

AF:

0.739

Gnomad SAS

AF:

0.487

Gnomad FIN

AF:

0.510

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.579

Gnomad OTH

AF:

0.553

GnomAD4 exome

AF:

0.549

AC:

7887

AN:

14378

Hom.:

2243

AF XY:

0.541

AC XY:

3986

AN XY:

7366

show subpopulations

African (AFR)

AF:

0.576

AC:

175

AN:

304

American (AMR)

AF:

0.398

AC:

322

AN:

810

Ashkenazi Jewish (ASJ)

AF:

0.649

AC:

231

AN:

356

East Asian (EAS)

AF:

0.738

AC:

608

AN:

824

South Asian (SAS)

AF:

0.428

AC:

303

AN:

708

European-Finnish (FIN)

AF:

0.498

AC:

457

AN:

918

Middle Eastern (MID)

AF:

0.533

AC:

AN:

European-Non Finnish (NFE)

AF:

0.556

AC:

5325

AN:

9580

Other (OTH)

AF:

0.531

AC:

434

AN:

818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

175

351

526

702

877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.576

AC:

87567

AN:

152042

Hom.:

25507

Cov.:

AF XY:

0.570

AC XY:

42339

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.622

AC:

25784

AN:

41476

American (AMR)

AF:

0.442

AC:

6752

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.633

AC:

2193

AN:

3466

East Asian (EAS)

AF:

0.740

AC:

3817

AN:

5158

South Asian (SAS)

AF:

0.486

AC:

2341

AN:

4814

European-Finnish (FIN)

AF:

0.510

AC:

5390

AN:

10570

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.579

AC:

39343

AN:

67950

Other (OTH)

AF:

0.549

AC:

1160

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1909

3819

5728

7638

9547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

752

1504

2256

3008

3760

<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:

0.578

Hom.:

83625

Bravo

AF:

0.574

Asia WGS

AF:

0.559

AC:

1945

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.5

(source)

DANN

Benign

0.44

PhyloP100

0.20

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over