Genetic Variant NM_000598.5:c.698G>T (chr7-45916600-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000598.5(IGFBP3):c.698G>T(p.Arg233Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP3	NM_000598.5 link	c.698G>T	p.Arg233Met	missense_variant	Exon 3 of 5	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 link	c.716G>T	p.Arg239Met	missense_variant	Exon 3 of 5		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 link	c.698G>T	p.Arg233Met	missense_variant	Exon 3 of 4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5 link	c.698G>T	p.Arg233Met	missense_variant	Exon 3 of 5	5	NM_000598.5	ENSP00000477772.2		P17936-1A6XND0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251490

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461346

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.716G>T (p.R239M) alteration is located in exon 3 (coding exon 3) of the IGFBP3 gene. This alteration results from a G to T substitution at nucleotide position 716, causing the arginine (R) at amino acid position 239 to be replaced by a methionine (M). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;T;D;.;T;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.071

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Uncertain

-0.014

MutationAssessor

Uncertain

2.8

.;.;M;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.2

D;.;D;D;.;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0090

D;.;D;D;.;D

Sift4G

Uncertain

0.014

D;T;T;T;T;D

Polyphen

0.99

D;.;D;.;.;.

Vest4

0.69

MutPred

0.62

.;.;Loss of solvent accessibility (P = 0.0058);.;.;.;

MVP

0.91

MPC

1.1

ClinPred

0.66

GERP RS

4.1

Varity_R

0.14

gMVP

0.73

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