4-57109921-C-T

Position:

chr4-57109921-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000295666.6(IGFBP7):c.431G>A(p.Gly144Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,557,532 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 7 hom. )

Consequence

IGFBP7
ENST00000295666.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

IGFBP7 (HGNC:5476): (insulin like growth factor binding protein 7) This gene encodes a member of the insulin-like growth factor (IGF)-binding protein (IGFBP) family. IGFBPs bind IGFs with high affinity, and regulate IGF availability in body fluids and tissues and modulate IGF binding to its receptors. This protein binds IGF-I and IGF-II with relatively low affinity, and belongs to a subfamily of low-affinity IGFBPs. It also stimulates prostacyclin production and cell adhesion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, and one variant has been associated with retinal arterial macroaneurysm (PMID:21835307). [provided by RefSeq, Dec 2011]

IGFBP7 links:

IGFBP7-AS1 (HGNC:40296): (IGFBP7 antisense RNA 1)

IGFBP7-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050709844).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IGFBP7	NM_001553.3 linkuse as main transcript	c.431G>A	p.Gly144Glu	missense_variant	1/5	ENST00000295666.6	NP_001544.1
IGFBP7-AS1	NR_034081.1 linkuse as main transcript	n.160C>T		non_coding_transcript_exon_variant	1/5
IGFBP7	NM_001253835.2 linkuse as main transcript	c.431G>A	p.Gly144Glu	missense_variant	1/4		NP_001240764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6 linkuse as main transcript	c.431G>A	p.Gly144Glu	missense_variant	1/5	1	NM_001553.3	ENSP00000295666	P2	Q16270-1
IGFBP7-AS1	ENST00000499667.6 linkuse as main transcript	n.160C>T		non_coding_transcript_exon_variant	1/5	1
IGFBP7-AS1	ENST00000508328.6 linkuse as main transcript	n.142C>T		non_coding_transcript_exon_variant	1/4	3
IGFBP7	ENST00000514062.2 linkuse as main transcript	c.431G>A	p.Gly144Glu	missense_variant	1/4	2		ENSP00000486293	A2	Q16270-2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152238

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:

0.00579

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00115

AC:

185

AN:

160438

Hom.:

AF XY:

0.00146

AC XY:

128

AN XY:

87714

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000380

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00753

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000447

GnomAD4 exome

AF:

0.000401

AC:

563

AN:

1405176

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

393

AN XY:

695562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000265

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00657

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.000528

GnomAD4 genome

AF:

0.000184

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74510

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:

0.00579

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000499

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.00376

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.431G>A (p.G144E) alteration is located in exon 1 (coding exon 1) of the IGFBP7 gene. This alteration results from a G to A substitution at nucleotide position 431, causing the glycine (G) at amino acid position 144 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

IGFBP7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

0.87

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.12

Sift

Benign

0.36

T;.

Sift4G

Benign

0.43

T;T

Polyphen

0.52

P;.

Vest4

0.65

MutPred

0.48

Gain of glycosylation at S142 (P = 0.0085);Gain of glycosylation at S142 (P = 0.0085);

MVP

0.36

MPC

1.1

ClinPred

0.067

GERP RS

2.0

Varity_R

0.15

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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