4-57109949-C-T

Position:

chr4-57109949-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000295666.6(IGFBP7):c.403G>A(p.Ala135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,554,400 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 3 hom. )

Consequence

IGFBP7
ENST00000295666.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.08

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058704615).

BP6

Variant 4-57109949-C-T is Benign according to our data. Variant chr4-57109949-C-T is described in ClinVar as [Benign]. Clinvar id is 3045248.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IGFBP7	NM_001553.3 linkuse as main transcript	c.403G>A	p.Ala135Thr	missense_variant	1/5	ENST00000295666.6	NP_001544.1
IGFBP7-AS1	NR_034081.1 linkuse as main transcript	n.188C>T		non_coding_transcript_exon_variant	1/5
IGFBP7	NM_001253835.2 linkuse as main transcript	c.403G>A	p.Ala135Thr	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.403G>A	p.Ala135Thr	missense_variant	1/5	1	NM_001553.3	ENSP00000295666	P2	Q16270-1
IGFBP7-AS1	ENST00000499667.6 linkuse as main transcript	n.188C>T		non_coding_transcript_exon_variant	1/5	1
IGFBP7-AS1	ENST00000508328.6 linkuse as main transcript	n.170C>T		non_coding_transcript_exon_variant	1/4	3
IGFBP7	ENST00000514062.2 linkuse as main transcript	c.403G>A	p.Ala135Thr	missense_variant	1/4	2		ENSP00000486293	A2	Q16270-2

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00130

AC:

200

AN:

153752

Hom.:

AF XY:

0.00133

AC XY:

112

AN XY:

84346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000773

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000398

Gnomad OTH exome

AF:

0.00255

GnomAD4 exome

AF:

0.000585

AC:

820

AN:

1402174

Hom.:

Cov.:

AF XY:

0.000598

AC XY:

415

AN XY:

693600

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.000240

Gnomad4 ASJ exome

AF:

0.0202

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.000565

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.000608

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.000851

AC:

ExAC

AF:

0.000656

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IGFBP7-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as 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

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.27

N;.

REVEL

Benign

0.050

Sift

Benign

0.68

T;.

Sift4G

Benign

0.69

T;T

Polyphen

0.47

P;.

Vest4

0.14

MVP

0.19

MPC

0.52

ClinPred

0.035

GERP RS

3.0

Varity_R

0.080

gMVP

0.30

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