Genetic Variant NM_000598.5:c.349G>A (chr7-45920792-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_000598.5(IGFBP3):c.349G>A(p.Ala117Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,418,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2404598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP3	NM_000598.5 link	c.349G>A	p.Ala117Thr	missense_variant	Exon 1 of 5	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 link	c.349G>A	p.Ala117Thr	missense_variant	Exon 1 of 5		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 link	c.349G>A	p.Ala117Thr	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.349G>A	p.Ala117Thr	missense_variant	Exon 1 of 5	5	NM_000598.5	ENSP00000477772.2		P17936-1A6XND0

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000474

AC:

AN:

1266564

Hom.:

Cov.:

AF XY:

0.00000645

AC XY:

AN XY:

620390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000159

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000487

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349G>A (p.A117T) alteration is located in exon 1 (coding exon 1) of the IGFBP3 gene. This alteration results from a G to A substitution at nucleotide position 349, causing the alanine (A) at amino acid position 117 to be replaced by a threonine (T). 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

0.083

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

T;T;T;.;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.66

T;T;T;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.2

.;.;M;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.98

N;.;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.12

T;.;T;T;.

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.99

D;.;P;.;.

Vest4

0.19

MutPred

0.26

.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;

MVP

0.72

MPC

0.78

ClinPred

0.78

GERP RS

1.9

Varity_R

0.068

gMVP

0.30

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