rs121909212

Variant names:

• chr5-136055770-C-A
• rs121909212
• NM_000358.3:c.1501C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-136055770-C-A
• chr5-136055770-C-G
• chr5-136055770-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P501S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: TGFBI NM_000358.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 6.00
• Publications: 44 publications found

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 Gene-Disease associations (from GenCC):

• epithelial-stromal TGFBI dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• granular corneal dystrophy type I

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• granular corneal dystrophy type II

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• lattice corneal dystrophy type I

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Reis-Bucklers corneal dystrophy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Thiel-Behnke corneal dystrophy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• epithelial basement membrane dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 5-136055770-C-A is Pathogenic according to our data. Variant chr5-136055770-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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. GnomAdExome4 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 GnomAdExome4. There are 187 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000358.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	NM_000358.3	MANE Select	c.1501C>A	p.Pro501Thr	missense	Exon 11 of 17	NP_000349.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	ENST00000442011.7	TSL:1 MANE Select	c.1501C>A	p.Pro501Thr	missense	Exon 11 of 17	ENSP00000416330.2
	TGFBI	ENST00000514554.5	TSL:5	c.652C>A	p.Pro218Thr	missense	Exon 5 of 9	ENSP00000421440.1
	TGFBI	ENST00000506699.5	TSL:2	n.2018C>A		non_coding_transcript_exon	Exon 11 of 17

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152222 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.000318 AC: 79 AN: 248114 AF XY: 0.000245

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 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.: 1 Cov.: 31 AF XY: 0.000257 AC XY: 187 AN XY: 726252

African (AFR) AF: 0.000149 AC: 5 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26110

East Asian (EAS) AF: 0.00759 AC: 301 AN: 39662

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85988

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53358

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1110994

Other (OTH) AF: 0.000282 AC: 17 AN: 60296

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152340 Hom.: 1 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000275 Hom.: 1

Bravo AF: 0.000268

ExAC AF: 0.000298 AC: 36

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy, lattice type 3A Pathogenic:1

Nov 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Corneal dystrophy Pathogenic:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).

not provided Pathogenic:1

Sep 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.63
Sift	Benign	0.043	D
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.97
MVP		0.94
MPC		0.14
ClinPred		0.18	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.88
Mutation Taster		=57/43	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909212; hg19: chr5-135391459;