Genetic Variant IGFBP3:p.Ala32Gly (chr7-45921046-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000598.5(IGFBP3):c.95C>G(p.Ala32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,441,040 control chromosomes in the GnomAD database, including 118,622 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.38 ( 11466 hom., cov: 33)

Exomes 𝑓: 0.40 ( 107156 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.359

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.1002727E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP3	NM_000598.5 link	c.95C>G	p.Ala32Gly	missense_variant	Exon 1 of 5	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 link	c.95C>G	p.Ala32Gly	missense_variant	Exon 1 of 5		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 link	c.95C>G	p.Ala32Gly	missense_variant	Exon 1 of 4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5 link	c.95C>G	p.Ala32Gly	missense_variant	Exon 1 of 5	5	NM_000598.5	ENSP00000477772.2		P17936-1A6XND0

Frequencies

GnomAD3 genomes

AF:

0.379

AC:

57281

AN:

151182

Hom.:

11477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.584

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.460

Gnomad EAS

AF:

0.751

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.350

Gnomad MID

AF:

0.474

Gnomad NFE

AF:

0.403

Gnomad OTH

AF:

0.386

GnomAD3 exomes

AF:

0.382

AC:

21599

AN:

56480

Hom.:

4633

AF XY:

0.389

AC XY:

12740

AN XY:

32772

show subpopulations

Gnomad AFR exome

AF:

0.310

Gnomad AMR exome

AF:

0.234

Gnomad ASJ exome

AF:

0.485

Gnomad EAS exome

AF:

0.782

Gnomad SAS exome

AF:

0.351

Gnomad FIN exome

AF:

0.381

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.402

AC:

518243

AN:

1289750

Hom.:

107156

Cov.:

AF XY:

0.400

AC XY:

254181

AN XY:

634912

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.263

Gnomad4 ASJ exome

AF:

0.475

Gnomad4 EAS exome

AF:

0.761

Gnomad4 SAS exome

AF:

0.345

Gnomad4 FIN exome

AF:

0.349

Gnomad4 NFE exome

AF:

0.401

Gnomad4 OTH exome

AF:

0.408

GnomAD4 genome

AF:

0.379

AC:

57274

AN:

151290

Hom.:

11466

Cov.:

AF XY:

0.377

AC XY:

27912

AN XY:

73960

show subpopulations

Gnomad4 AFR

AF:

0.311

Gnomad4 AMR

AF:

0.320

Gnomad4 ASJ

AF:

0.460

Gnomad4 EAS

AF:

0.751

Gnomad4 SAS

AF:

0.361

Gnomad4 FIN

AF:

0.350

Gnomad4 NFE

AF:

0.403

Gnomad4 OTH

AF:

0.383

Alfa

AF:

0.211

Hom.:

419

Bravo

AF:

0.377

ExAC

AF:

0.283

AC:

3944

Asia WGS

AF:

0.484

AC:

1665

AN:

3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.9

DANN

Benign

0.95

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.47

T;T

MetaRNN

Benign

0.0000041

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.017

Sift

Benign

0.38

T;T

Sift4G

Benign

0.91

T;T

Polyphen

0.0060

B;.

Vest4

0.059

MPC

0.54

ClinPred

0.0019

GERP RS

0.63

Varity_R

0.036

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over