Genetic Variant IGFBP5:p.Pro17Arg (chr2-216694726-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000599.4(IGFBP5):c.50C>G(p.Pro17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,306,632 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: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

IGFBP5
NM_000599.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.733

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05333048).

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4 link	c.50C>G	p.Pro17Arg	missense_variant	Exon 1 of 4	ENST00000233813.5	NP_000590.1	P24593
IGFBP-AS1	NR_187138.1 link	n.281G>C		non_coding_transcript_exon_variant	Exon 1 of 6
IGFBP-AS1	NR_187139.1 link	n.281G>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.50C>G	p.Pro17Arg	missense_variant	Exon 1 of 4	1	NM_000599.4	ENSP00000233813.4		P24593

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

90574

AF XY:

0.0000201

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1306632

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

636808

show subpopulations

African (AFR)

AF:

0.0000384

AC:

AN:

26072

American (AMR)

AF:

0.00

AC:

AN:

22050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18388

East Asian (EAS)

AF:

0.00

AC:

AN:

32894

South Asian (SAS)

AF:

0.0000160

AC:

AN:

62398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5172

European-Non Finnish (NFE)

AF:

0.0000221

AC:

AN:

1042050

Other (OTH)

AF:

0.0000186

AC:

AN:

53746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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

ExAC

AF:

0.00000864

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.50C>G (p.P17R) alteration is located in exon 1 (coding exon 1) of the IGFBP5 gene. This alteration results from a C to G substitution at nucleotide position 50, causing the proline (P) at amino acid position 17 to be replaced by an arginine (R). 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

Benign

0.093

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.40

N;.

PhyloP100

0.73

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.034

Sift

Benign

0.53

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0

B;.

Vest4

0.097

MVP

0.14

MPC

0.67

ClinPred

0.031

GERP RS

3.6

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.048

gMVP

0.35

Mutation Taster

=88/12

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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2-216694726-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over