Variant 7-45917251-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000598.5(IGFBP3):c.592C>G(p.Gln198Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,613,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

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:

IGFBP3 (HGNC:):

IGFBP3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08280349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5 linkuse as main transcript	c.592C>G	p.Gln198Glu	missense_variant	2/5	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 linkuse as main transcript	c.610C>G	p.Gln204Glu	missense_variant	2/5		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 linkuse as main transcript	c.592C>G	p.Gln198Glu	missense_variant	2/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5 linkuse as main transcript	c.592C>G	p.Gln198Glu	missense_variant	2/5	5	NM_000598.5	ENSP00000477772.2		P17936-1A6XND0

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251486

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461758

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000112

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.610C>G (p.Q204E) alteration is located in exon 2 (coding exon 2) of the IGFBP3 gene. This alteration results from a C to G substitution at nucleotide position 610, causing the glutamine (Q) at amino acid position 204 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;T;T;.;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.0043

MetaRNN

Benign

0.083

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

.;.;M;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.83

N;.;N;N;.;N

REVEL

Benign

0.11

Sift

Benign

0.034

D;.;T;T;.;D

Sift4G

Benign

0.43

T;T;T;T;T;T

Polyphen

0.61

P;.;B;.;.;.

Vest4

0.20

MVP

0.65

MPC

1.0

ClinPred

0.084

GERP RS

5.3

Varity_R

0.14

gMVP

0.36

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over