5-136062674-G-C

Position:

chr5-136062674-G-C

Variant summary

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

The NM_000358.3(TGFBI):c.1998G>C(p.Arg666Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,567,842 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

TGFBI
NM_000358.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: -0.483

Variant links:

Genes affected

TGFBI (HGNC:11771): (transforming growth factor beta induced) This gene encodes an RGD-containing protein that binds to type I, II and IV collagens. The RGD motif is found in many extracellular matrix proteins modulating cell adhesion and serves as a ligand recognition sequence for several integrins. This protein plays a role in cell-collagen interactions and may be involved in endochondrial bone formation in cartilage. The protein is induced by transforming growth factor-beta and acts to inhibit cell adhesion. Mutations in this gene are associated with multiple types of corneal dystrophy. [provided by RefSeq, Jul 2008]

TGFBI links:

TGFBI (HGNC:):

TGFBI 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=0.0059023798).

BS2

High AC in GnomAd4 at 157 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBI	NM_000358.3 linkuse as main transcript	c.1998G>C	p.Arg666Ser	missense_variant	16/17	ENST00000442011.7	NP_000349.1	Q15582A0A0S2Z4Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7 linkuse as main transcript	c.1998G>C	p.Arg666Ser	missense_variant	16/17	1	NM_000358.3	ENSP00000416330.2		Q15582

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00119

AC:

217

AN:

182164

Hom.:

AF XY:

0.00115

AC XY:

111

AN XY:

96844

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000896

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.00142

AC:

2015

AN:

1415554

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

961

AN XY:

699552

show subpopulations

Gnomad4 AFR exome

AF:

0.000276

Gnomad4 AMR exome

AF:

0.00176

Gnomad4 ASJ exome

AF:

0.0000787

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000930

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.00135

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152288

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00182

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.000861

AC:

102

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TGFBI: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	- -

Epithelial basement membrane dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2006

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Corneal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.49

N;D

REVEL

Uncertain

0.46

Sift

Benign

0.45

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0

B;.

Vest4

0.20

MutPred

0.80

Loss of helix (P = 0.028);.;

MVP

0.82

MPC

0.047

ClinPred

0.017

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.78

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