7-45921119-G-C

Position:

chr7-45921119-G-C

Variant summary

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

The NM_000598.5(IGFBP3):c.22C>G(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,496,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37

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=0.19473526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/5	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/5		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IGFBP3	ENST00000613132.5 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/5	5	NM_000598.5	ENSP00000477772.2	P17936-1A6XND0
IGFBP3	ENST00000381083.9 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/5	5		ENSP00000370473.4	P17936-2
IGFBP3	ENST00000381086.9 linkuse as main transcript	c.9+13C>G		intron_variant		2		ENSP00000370476.4	B3KWK7
IGFBP3	ENST00000448817.1 linkuse as main transcript	c.73+508C>G		intron_variant		4		ENSP00000389668.1	C9JMX4

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000730

AC:

AN:

95934

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

54002

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000589

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000124

AC:

167

AN:

1344550

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

663260

show subpopulations

Gnomad4 AFR exome

AF:

0.0000740

Gnomad4 AMR exome

AF:

0.000156

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000302

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.000125

GnomAD4 genome

AF:

0.000118

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000117

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

Sep 14, 2023

The c.22C>G (p.L8V) alteration is located in exon 1 (coding exon 1) of the IGFBP3 gene. This alteration results from a C to G substitution at nucleotide position 22, causing the leucine (L) at amino acid position 8 to be replaced by a valine (V). 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

0.063

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

T;T;.;T

Eigen

Benign

-0.023

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.43

T;T;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

.;L;L;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.57

.;N;N;.

REVEL

Benign

0.061

Sift

Benign

0.058

.;T;T;.

Sift4G

Benign

0.12

T;D;D;T

Polyphen

0.97

.;D;.;.

Vest4

0.12

MutPred

0.26

Gain of MoRF binding (P = 0.0936);Gain of MoRF binding (P = 0.0936);Gain of MoRF binding (P = 0.0936);Gain of MoRF binding (P = 0.0936);

MVP

0.63

MPC

0.34

ClinPred

0.076

GERP RS

3.9

Varity_R

0.062

gMVP

0.60

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