Genetic Variant NM_000599.4:c.115C>G (chr2-216694661-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000599.4(IGFBP5):c.115C>G(p.Pro39Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000728 in 1,374,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

IGFBP5
NM_000599.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.48

Publications

0 publications found

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40887684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4 link	c.115C>G	p.Pro39Ala	missense_variant	Exon 1 of 4	ENST00000233813.5	NP_000590.1	P24593
IGFBP-AS1	NR_187138.1 link	n.216G>C		non_coding_transcript_exon_variant	Exon 1 of 6
IGFBP-AS1	NR_187139.1 link	n.216G>C		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.115C>G	p.Pro39Ala	missense_variant	Exon 1 of 4	1	NM_000599.4	ENSP00000233813.4		P24593

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1374288

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

676408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29146

American (AMR)

AF:

0.00

AC:

AN:

32650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22086

East Asian (EAS)

AF:

0.00

AC:

AN:

35624

South Asian (SAS)

AF:

0.00

AC:

AN:

73380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1072238

Other (OTH)

AF:

0.00

AC:

AN:

56658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

0.098

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

5.5

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

D;N

REVEL

Benign

0.24

Sift

Benign

0.47

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.63

P;.

Vest4

0.16

MutPred

0.61

Loss of glycosylation at P39 (P = 0.0411);Loss of glycosylation at P39 (P = 0.0411);

MVP

0.61

MPC

1.6

ClinPred

0.99

GERP RS

3.6

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.18

gMVP

0.78

Mutation Taster

=53/47

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over