Genetic Variant IGFBP5:p.Ser105Ile (chr2-216694462-C-A) – 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.314G>T(p.Ser105Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,414 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. 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. S105N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

IGFBP5
NM_000599.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.945

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14640906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP5	NM_000599.4 link	c.314G>T	p.Ser105Ile	missense_variant	Exon 1 of 4	ENST00000233813.5	NP_000590.1	P24593
IGFBP-AS1	NR_187138.1 link	n.17C>A		non_coding_transcript_exon_variant	Exon 1 of 6
IGFBP-AS1	NR_187139.1 link	n.17C>A		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.314G>T	p.Ser105Ile	missense_variant	Exon 1 of 4	1	NM_000599.4	ENSP00000233813.4		P24593

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707818

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:

31888

American (AMR)

AF:

0.00

AC:

AN:

40328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24808

East Asian (EAS)

AF:

0.00

AC:

AN:

37996

South Asian (SAS)

AF:

0.00

AC:

AN:

81204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1099100

Other (OTH)

AF:

0.00

AC:

AN:

59120

⚠️ 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.079

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

L;.

PhyloP100

0.94

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.019

Sift

Benign

0.039

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.085

B;.

Vest4

0.082

MutPred

0.36

Loss of ubiquitination at K104 (P = 0.0313);Loss of ubiquitination at K104 (P = 0.0313);

MVP

0.26

MPC

0.76

ClinPred

0.32

GERP RS

1.5

PromoterAI

0.068

Neutral

(source)

Varity_R

0.11

gMVP

0.58

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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chr2-216694462-C-A

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