Genetic Variant IGFBP5:p.Arg107Ser (chr2-216694457-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000599.4(IGFBP5):c.319C>A(p.Arg107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IGFBP5
NM_000599.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.774

Variant links:

Genes affected

IGFBP5 (HGNC:5474): (insulin like growth factor binding protein 5) Enables insulin-like growth factor I binding activity. Involved in several processes, including cellular response to cAMP; regulation of smooth muscle cell migration; and regulation of smooth muscle cell proliferation. Part of insulin-like growth factor ternary complex. Biomarker of pulmonary fibrosis. [provided by Alliance of Genome Resources, Apr 2022]

IGFBP5 links:

TESHL (HGNC:52740): (testicular germ cell expressed HSF2 interacting lncRNA)

TESHL links:

IGFBP-AS1 (HGNC:55655): (IGFBP5 antisense RNA 1)

IGFBP-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09506723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4 link	c.319C>A	p.Arg107Ser	missense_variant	Exon 1 of 4	ENST00000233813.5	NP_000590.1	P24593
IGFBP-AS1	NR_187138.1 link	n.12G>T		non_coding_transcript_exon_variant	Exon 1 of 6
IGFBP-AS1	NR_187139.1 link	n.12G>T		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP5	ENST00000233813.5 link	c.319C>A	p.Arg107Ser	missense_variant	Exon 1 of 4	1	NM_000599.4	ENSP00000233813.4		P24593

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1422376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704964

African (AFR)

AF:

0.00

AC:

AN:

31684

American (AMR)

AF:

0.00

AC:

AN:

39674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24604

East Asian (EAS)

AF:

0.00

AC:

AN:

37728

South Asian (SAS)

AF:

0.00

AC:

AN:

80606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096930

Other (OTH)

AF:

0.00

AC:

AN:

58942

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.319C>A (p.R107S) alteration is located in exon 1 (coding exon 1) of the IGFBP5 gene. This alteration results from a C to A substitution at nucleotide position 319, causing the arginine (R) at amino acid position 107 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

Uncertain

0.54

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.095

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.77

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.050

Sift

Benign

0.50

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.14

B;.

Vest4

0.11

MutPred

0.38

Loss of MoRF binding (P = 0.0094);Loss of MoRF binding (P = 0.0094);

MVP

0.44

MPC

0.72

ClinPred

0.33

GERP RS

2.6

PromoterAI

0.0024

Neutral

(source)

Varity_R

0.10

gMVP

0.53

Mutation Taster

=85/15

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over