Variant 7-45888770-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000596.4(IGFBP1):c.118C>T(p.Leu40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000831 in 1,565,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

IGFBP1
NM_000596.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.445

Variant links:

Genes affected

IGFBP1 (HGNC:5469): (insulin like growth factor binding protein 1) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP N-terminal domain and a thyroglobulin type-I domain. The encoded protein, mainly expressed in the liver, circulates in the plasma and binds both insulin-like growth factors (IGFs) I and II, prolonging their half-lives and altering their interaction with cell surface receptors. This protein is important in cell migration and metabolism. Low levels of this protein may be associated with impaired glucose tolerance, vascular disease and hypertension in human patients. [provided by RefSeq, Aug 2017]

IGFBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGFBP1	NM_000596.4 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/4	ENST00000275525.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IGFBP1	ENST00000275525.8 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/4	1	NM_000596.4	P4
IGFBP1	ENST00000457280.5 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/4	5		A2
IGFBP1	ENST00000468955.1 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/3	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000115

AC:

AN:

173230

Hom.:

AF XY:

0.0000104

AC XY:

AN XY:

95868

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000779

AC:

AN:

1412894

Hom.:

Cov.:

AF XY:

0.00000856

AC XY:

AN XY:

700744

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000100

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.00000882

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.118C>T (p.L40F) alteration is located in exon 1 (coding exon 1) of the IGFBP1 gene. This alteration results from a C to T substitution at nucleotide position 118, causing the leucine (L) at amino acid position 40 to be replaced by a phenylalanine (F). 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

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.49

T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.9

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.15

T;T;D

Sift4G

Benign

0.10

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.085

MutPred

0.46

Loss of disorder (P = 0.0879);Loss of disorder (P = 0.0879);Loss of disorder (P = 0.0879);

MVP

0.87

MPC

0.62

ClinPred

0.12

GERP RS

4.1

Varity_R

0.044

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over