5-136046407-G-A

Position:

chr5-136046407-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The ENST00000442011.7(TGFBI):c.371G>A(p.Arg124His) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TGFBI
ENST00000442011.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.76

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 12 ACMG points.

PM1

In a domain FAS1 1 (size 133) in uniprot entity BGH3_HUMAN there are 37 pathogenic changes around while only 4 benign (90%) in ENST00000442011.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-136046406-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 5-136046407-G-A is Pathogenic according to our data. Variant chr5-136046407-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-136046407-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBI	NM_000358.3 linkuse as main transcript	c.371G>A	p.Arg124His	missense_variant	4/17	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7 linkuse as main transcript	c.371G>A	p.Arg124His	missense_variant	4/17	1	NM_000358.3	ENSP00000416330	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

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:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000402

AC:

AN:

249054

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000501

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000471

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Avellino corneal dystrophy

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 09, 2024	Criteria applied: PS4,PM5_STR,PS3_MOD,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.371G>A(p.Arg124His) in the TGFBI gene has been reported previously in individual(s) with autosomal dominant corneal dystrophy (Nagano C, et al., 2019; Jozaei R, et al.,2022). Experimental studies have shown that this missense change affects TGFBI function (Nielsen NS, et al., 2021). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (Grothe HL, et al., 2013; Munier FL, et al., 2002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is reported with the allele frequency 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arginine at position 124 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 20, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 124 of the TGFBI protein (p.Arg124His). This variant is present in population databases (rs121909211, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant corneal dystrophy (PMID: 11923233). ClinVar contains an entry for this variant (Variation ID: 7869). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TGFBI function (PMID: 26197481, 34097874). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10798644, 11923233, 23559853). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

Lattice corneal dystrophy Type I

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22850414, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007872, PMID:10425035,9054935,9780098, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, 3CNET: 0.902, PP3_P). A missense variant is a common mechanism associated with Corneal dystrophy (PP2_P). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.74

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.77

Sift

Uncertain

0.018

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.76

MutPred

0.55

Loss of phosphorylation at T125 (P = 0.1017);

MVP

0.98

MPC

0.33

ClinPred

0.44

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.79

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