dbSNP rs909110022: IGFBP3:p.Gly21Trp (chr7-45921080-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000598.5(IGFBP3):c.61G>T(p.Gly21Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

IGFBP3
NM_000598.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.195616).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000598.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP3	NM_000598.5	MANE Select	c.61G>T	p.Gly21Trp	missense	Exon 1 of 5	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.61G>T	p.Gly21Trp	missense	Exon 1 of 5	NP_001013416.1	P17936-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGFBP3	ENST00000613132.5	TSL:5 MANE Select	c.61G>T	p.Gly21Trp	missense	Exon 1 of 5	ENSP00000477772.2	P17936-1
IGFBP3	ENST00000908406.1		c.61G>T	p.Gly21Trp	missense	Exon 1 of 6	ENSP00000578465.1
IGFBP3	ENST00000381083.9	TSL:5	c.61G>T	p.Gly21Trp	missense	Exon 1 of 5	ENSP00000370473.4	P17936-2

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

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:

0.000480

GnomAD2 exomes

AF:

0.0000436

AC:

AN:

68834

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1308582

Hom.:

Cov.:

AF XY:

0.00000465

AC XY:

AN XY:

645146

show subpopulations

African (AFR)

AF:

0.0000386

AC:

AN:

25940

American (AMR)

AF:

0.000169

AC:

AN:

23732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22350

East Asian (EAS)

AF:

0.00

AC:

AN:

28118

South Asian (SAS)

AF:

0.00

AC:

AN:

71234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046366

Other (OTH)

AF:

0.0000740

AC:

AN:

54054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.000525

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67890

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000106

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.37

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.57

M_CAP

Benign

0.058

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.97

PhyloP100

2.3

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.60

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Benign

0.084

Polyphen

0.99

Vest4

0.41

MutPred

0.44

Loss of disorder (P = 0.0116)

MVP

0.51

MPC

0.40

ClinPred

0.18

GERP RS

1.3

PromoterAI

0.018

Neutral

(source)

Varity_R

0.053

gMVP

0.61

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over