rs121909212

chr5-136055770-C-Achr5-136055770-C-Gchr5-136055770-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM5 PP5 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 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 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.00

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]

ACMG classification

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: {Uncertain_significance=1, Likely_pathogenic=2}. 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 GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBI	NM_000358.3	c.1501C>A	p.Pro501Thr	missense_variant	11/17	ENST00000442011.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBI	ENST00000442011.7	c.1501C>A	p.Pro501Thr	missense_variant	11/17	1	NM_000358.3	P1

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

GnomAD3 exomes AF: 0.000318 AC: 79 AN: 248114 Hom.: 0 AF XY: 0.000245 AC XY: 33 AN XY: 134596

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

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

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.: 0

Bravo AF: 0.000268

ExAC AF: 0.000298 AC: 36

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

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

Invitae

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	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
MutationTaster	Benign	1.0	A;A
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

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

Other links and lift over

dbSNP: rs121909212; hg19: chr5-135391459;