5-136056780-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000358.3(TGFBI):c.1663C>T(p.Arg555Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R555Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TGFBI
NM_000358.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a domain FAS1 4 (size 130) in uniprot entity BGH3_HUMAN there are 77 pathogenic changes around while only 2 benign (97%) in NM_000358.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-136056781-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 5-136056780-C-T is Pathogenic according to our data. Variant chr5-136056780-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-136056780-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3 link	c.1663C>T	p.Arg555Trp	missense_variant	Exon 12 of 17	ENST00000442011.7	NP_000349.1	Q15582A0A0S2Z4Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7 link	c.1663C>T	p.Arg555Trp	missense_variant	Exon 12 of 17	1	NM_000358.3	ENSP00000416330.2		Q15582

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727014

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 555 of the TGFBI protein (p.Arg555Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant corneal dystrophy (PMID: 1264234, 9054935, 11923233, 21264234). It has also been observed to segregate with disease in related individuals. This variant is also known as 1710C>T. ClinVar contains an entry for this variant (Variation ID: 7866). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TGFBI protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TGFBI function (PMID: 23559853). This variant disrupts the p.Arg555 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21135107, 22355247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBI: PP1:Strong, PM2, PM5, PM6, PS4:Moderate, BP4 -

Sep 19, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that p.(R555W) leads to increased expression and aggregation of the TGFBI protein (Runager et al., 2011; Yam et al., 2012; Underhaug et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16087849, 23828476, 19948560, 19337156, 23991378, 21836353, 22355247, 20664689, 21264234, 16767671, 22746317, 22575305, 23559853, 9054935, 12709742, 26305369, 26464103, 18650671, 9744382, 30915236, 34097874, 14576527, 16118514, 22605926, 11923233, 21135107, 24129074, 22850414, 35985662, 33816482, 9727509) -

Groenouw corneal dystrophy type I

Pathogenic:2

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 22, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lattice corneal dystrophy Type I

Pathogenic:1

May 03, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Reis-Bucklers' corneal dystrophy;C0521723:Epithelial basement membrane dystrophy;C1275685:Avellino corneal dystrophy;C1562894:Thiel-Behnke corneal dystrophy;C1641846:Groenouw corneal dystrophy type I;C1690006:Lattice corneal dystrophy Type I;C1837974:Corneal dystrophy, lattice type 3A

Pathogenic:1

May 07, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo c.1663C>T (p.Arg555Trp) variant identified in the TGFBI gene substitutes an Arginine for Tryptophan at amino acid 555/684 (exon12/17). This amino acid is not well conserved in mammals. This variant is found with low frequency in gnomAD(v3.1.1) (1 heterozygote, 0 homozygotes; allele frequency:6.57e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT;score:0.018) and Pathogenic (REVEL; score:0.6399) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:7866), and has been reported in many individuals in the literature with corneal dystrophy, and is a well-known pathogenic variant associated with corneal dystrophy [PMID:33816482; PMID:33513810; others]. The de novo c.1663C>T (p.Arg555Trp) variant identified in the TGFBI gene is reported as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

0.095

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.084

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.64

Sift

Uncertain

0.018

Sift4G

Benign

0.070

Polyphen

1.0

Vest4

0.77

MutPred

0.86

Loss of disorder (P = 0.004);

MVP

0.96

MPC

0.22

ClinPred

0.92

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.83

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