Genetic Variant IGFBP1:p.Cys230Cys (chr7-45893001-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000596.4(IGFBP1):c.690C>T(p.Cys230Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,611,946 control chromosomes in the GnomAD database, including 3,364 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 0.084 ( 904 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2460 hom. )

Consequence

IGFBP1
NM_000596.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.356

Publications

26 publications found

Variant links:

Genes affected

IGFBP1 (HGNC:5469): (insulin like growth factor binding protein 1) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP N-terminal domain and a thyroglobulin type-I domain. The encoded protein, mainly expressed in the liver, circulates in the plasma and binds both insulin-like growth factors (IGFs) I and II, prolonging their half-lives and altering their interaction with cell surface receptors. This protein is important in cell migration and metabolism. Low levels of this protein may be associated with impaired glucose tolerance, vascular disease and hypertension in human patients. [provided by RefSeq, Aug 2017]

IGFBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP7

Synonymous conserved (PhyloP=-0.356 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP1	NM_000596.4 link	c.690C>T	p.Cys230Cys	synonymous_variant	Exon 4 of 4	ENST00000275525.8	NP_000587.1	P08833

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGFBP1	ENST00000275525.8 link	c.690C>T	p.Cys230Cys	synonymous_variant	Exon 4 of 4	1	NM_000596.4	ENSP00000275525.3	P08833
IGFBP1	ENST00000457280.5 link	c.684C>T	p.Cys228Cys	synonymous_variant	Exon 4 of 4	5		ENSP00000413511.1	C9JXF9
IGFBP1	ENST00000468955.1 link	c.561C>T	p.Cys187Cys	synonymous_variant	Exon 3 of 3	5		ENSP00000417069.1	C9J6H2

Frequencies

GnomAD3 genomes

AF:

0.0838

AC:

12746

AN:

152088

Hom.:

899

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0662

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0409

Gnomad FIN

AF:

0.0557

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0464

Gnomad OTH

AF:

0.0626

GnomAD2 exomes

AF:

0.0617

AC:

15522

AN:

251394

AF XY:

0.0564

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.00844

Gnomad EAS exome

AF:

0.00321

Gnomad FIN exome

AF:

0.0604

Gnomad NFE exome

AF:

0.0497

Gnomad OTH exome

AF:

0.0500

GnomAD4 exome

AF:

0.0514

AC:

75089

AN:

1459740

Hom.:

2460

Cov.:

AF XY:

0.0503

AC XY:

36530

AN XY:

726282

show subpopulations

African (AFR)

AF:

0.190

AC:

6364

AN:

33414

American (AMR)

AF:

0.104

AC:

4639

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26130

East Asian (EAS)

AF:

0.00270

AC:

107

AN:

39694

South Asian (SAS)

AF:

0.0422

AC:

3632

AN:

86148

European-Finnish (FIN)

AF:

0.0605

AC:

3226

AN:

53358

Middle Eastern (MID)

AF:

0.0253

AC:

140

AN:

5524

European-Non Finnish (NFE)

AF:

0.0485

AC:

53848

AN:

1110458

Other (OTH)

AF:

0.0483

AC:

2912

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

3089

6178

9267

12356

15445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2128

4256

6384

8512

10640

<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:

0.0839

AC:

12774

AN:

152206

Hom.:

904

Cov.:

AF XY:

0.0815

AC XY:

6061

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.183

AC:

7589

AN:

41500

American (AMR)

AF:

0.0669

AC:

1023

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00270

AC:

AN:

5182

South Asian (SAS)

AF:

0.0404

AC:

195

AN:

4832

European-Finnish (FIN)

AF:

0.0557

AC:

589

AN:

10582

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0463

AC:

3150

AN:

68022

Other (OTH)

AF:

0.0619

AC:

131

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

573

1146

1720

2293

2866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0595

Hom.:

1349

Bravo

AF:

0.0909

Asia WGS

AF:

0.0400

AC:

141

AN:

3478

EpiCase

AF:

0.0416

EpiControl

AF:

0.0414

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.4

(source)

DANN

Benign

0.65

PhyloP100

-0.36

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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