dbSNP rs79982277: IGFBP4:p.Asp119Glu (chr17-40452992-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001552.3(IGFBP4):c.357C>A(p.Asp119Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D119D) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IGFBP4
NM_001552.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.133

Publications

0 publications found

Variant links:

Genes affected

IGFBP4 (HGNC:5473): (insulin like growth factor binding protein 4) 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 binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors. [provided by RefSeq, Jul 2008]

IGFBP4 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05883187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP4	NM_001552.3 link	c.357C>A	p.Asp119Glu	missense_variant	Exon 2 of 4	ENST00000269593.5	NP_001543.2	P22692-1A0A024R1U8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP4	ENST00000269593.5 link	c.357C>A	p.Asp119Glu	missense_variant	Exon 2 of 4	1	NM_001552.3	ENSP00000269593.4		P22692-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1396300

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690594

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30894

American (AMR)

AF:

0.00

AC:

AN:

37256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24526

East Asian (EAS)

AF:

0.00

AC:

AN:

35138

South Asian (SAS)

AF:

0.00

AC:

AN:

78098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1074838

Other (OTH)

AF:

0.00

AC:

AN:

57602

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.4

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.22

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.57

M_CAP

Benign

0.0054

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.35

PhyloP100

0.13

PrimateAI

Benign

0.43

PROVEAN

Benign

0.11

REVEL

Benign

0.036

Sift

Benign

0.88

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.14

MutPred

0.20

Gain of glycosylation at K118 (P = 0.1878);

MVP

0.23

MPC

0.63

ClinPred

0.12

GERP RS

0.074

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.27

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over