Variant 4-57031325-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000295666.6(IGFBP7):c.841G>A(p.Glu281Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,602,136 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

IGFBP7
ENST00000295666.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00950107).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP7	NM_001553.3 linkuse as main transcript	c.841G>A	p.Glu281Lys	missense_variant	5/5	ENST00000295666.6	NP_001544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6 linkuse as main transcript	c.841G>A	p.Glu281Lys	missense_variant	5/5	1	NM_001553.3	ENSP00000295666	P2	Q16270-1
IGFBP7	ENST00000512512.3 linkuse as main transcript	n.481G>A		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

150774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000884

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000303

AC:

AN:

247700

Hom.:

AF XY:

0.000306

AC XY:

AN XY:

134152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00359

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000427

Gnomad FIN exome

AF:

0.000103

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000209

AC:

303

AN:

1451246

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

165

AN XY:

722532

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00315

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000640

Gnomad4 FIN exome

AF:

0.0000593

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000366

GnomAD4 genome

AF:

0.000146

AC:

AN:

150890

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

73566

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000627

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000884

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000297

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain: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

Oct 12, 2021

The c.841G>A (p.E281K) alteration is located in exon 5 (coding exon 5) of the IGFBP7 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the glutamic acid (E) at amino acid position 281 to be replaced by a lysine (K). 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

0.088

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.67

M_CAP

Benign

0.012

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Uncertain

0.014

Sift4G

Uncertain

0.035

Polyphen

0.0

Vest4

0.13

MVP

0.58

MPC

0.48

ClinPred

0.040

GERP RS

1.1

Varity_R

0.077

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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