Variant 7-45920948-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000598.5(IGFBP3):c.193C>T(p.Pro65Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000036 in 1,388,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.19

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 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/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5 linkuse as main transcript	c.193C>T	p.Pro65Ser	missense_variant	1/5	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 linkuse as main transcript	c.193C>T	p.Pro65Ser	missense_variant	1/5		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 linkuse as main transcript	c.193C>T	p.Pro65Ser	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.193C>T	p.Pro65Ser	missense_variant	1/5	5	NM_000598.5	ENSP00000477772.2	P17936-1A6XND0
IGFBP3	ENST00000381083.9 linkuse as main transcript	c.193C>T	p.Pro65Ser	missense_variant	1/5	5		ENSP00000370473.4	P17936-2
IGFBP3	ENST00000381086.9 linkuse as main transcript	c.10-108C>T		intron_variant		2		ENSP00000370476.4	B3KWK7
IGFBP3	ENST00000448817.1 linkuse as main transcript	c.73+679C>T		intron_variant		4		ENSP00000389668.1	C9JMX4

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000323

AC:

AN:

1236602

Hom.:

Cov.:

AF XY:

0.00000330

AC XY:

AN XY:

606032

show subpopulations

Gnomad4 AFR exome

AF:

0.0000814

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.91e-7

Gnomad4 OTH exome

AF:

0.0000197

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74114

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.193C>T (p.P65S) alteration is located in exon 1 (coding exon 1) of the IGFBP3 gene. This alteration results from a C to T substitution at nucleotide position 193, causing the proline (P) at amino acid position 65 to be replaced by a serine (S). 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

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;D;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Uncertain

0.038

MutationAssessor

Pathogenic

3.2

.;M;M;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.7

.;D;D;.

REVEL

Uncertain

0.44

Sift

Uncertain

0.0040

.;D;D;.

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.99

.;D;.;.

Vest4

0.45

MutPred

0.60

.;Gain of glycosylation at P65 (P = 0.0093);Gain of glycosylation at P65 (P = 0.0093);.;

MVP

0.94

MPC

1.1

ClinPred

1.0

GERP RS

4.0

Varity_R

0.59

gMVP

0.64

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