rs121909212

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM5PP5BP4BS1_SupportingBS2

The NM_000358.3(TGFBI):c.1501C>A(p.Pro501Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000264 in 1,612,638 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P501S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

TGFBI
NM_000358.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.00

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 Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-136055770-C-T is described in Lovd as [Pathogenic].

PP5

Variant 5-136055770-C-A is Pathogenic according to our data. Variant chr5-136055770-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7871.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chr5-136055770-C-A is described in Lovd as [Pathogenic]. Variant chr5-136055770-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.16483247). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000267 (390/1460298) while in subpopulation EAS AF= 0.00759 (301/39662). AF 95% confidence interval is 0.00688. There are 1 homozygotes in gnomad4_exome. There are 187 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBI	NM_000358.3 linkuse as main transcript	c.1501C>A	p.Pro501Thr	missense_variant	11/17	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.1501C>A	p.Pro501Thr	missense_variant	11/17	1	NM_000358.3	ENSP00000416330	P1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000318

AC:

AN:

248114

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

134596

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00390

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000267

AC:

390

AN:

1460298

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

187

AN XY:

726252

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00759

Gnomad4 SAS exome

AF:

0.0000698

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000230

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00425

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000265

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.000298

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Corneal dystrophy, lattice type 3A

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2002

- -

Corneal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The TGFBI c.1501C>A (p.Pro501Thr) missense variant has been reported in a heterozygous state in a total of 21 individuals with lattice corneal dystrophy type IIIA, a late-onset condition which manifests after the seventh decade of life (Yamamoto et al. 1998; Tsujikawa et al. 2002; Yu et al. 2006; Long et al. 2011; Kojima et al. 2013). Nine of these individuals were from three families (Yamamoto et al. 1998). The p.Pro501Thr variant is described as a founder variant in the Japanese and Chinese populations (Tsujikawa et al. 2002; Yu et al. 2006). This variant was also detected in a heterozygous state in three additional individuals, two with Fuchs endothelial corneal dystrophy and one with Thiel-Behnke corneal dystrophy (Chae et al. 2016). The p.Pro501Thr variant was also present in five unaffected individuals in a heterozygous state, which the authors suggest may be attributed to the late-onset of the disease or due to reduced penetrance (Ha et al. 2000; Chae et al. 2016). The p.Pro501Thr variant was absent from six unaffected family members and at least 150 control individuals (Yamamoto et al. 1998; Tsujikawa et al. 2002), but is reported at a frequency of 0.00404 in the East Asian population of the Exome Aggregation Consortium. In addition, there is one individual with the variant in a homozygous state in the Genome Aggregation Database. Based on collective evidence, the p.Pro501Thr variant is classified as likely pathogenic for autosomal dominant corneal dystrophy. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2021

This sequence change replaces proline with threonine at codon 501 of the TGFBI protein (p.Pro501Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs121909212, ExAC 0.4%). This variant has been observed in individual(s) with lattice corneal dystrophy type IIIA, often with very late onset (PMID: 9497262, 10832717, 11024425, 21462384, 23884333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7871). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.045

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.63

Sift

Benign

0.043

Sift4G

Benign

0.26

Polyphen

1.0

Vest4

0.97

MVP

0.94

MPC

0.14

ClinPred

0.18

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.88

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