rs121909209

chr5-136056781-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000358.3(TGFBI):c.1664G>A(p.Arg555Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,396 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. R555W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGFBI NM_000358.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.04

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 3) in uniprot entity BGH3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr5-136056780-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 5-136056781-G-A is Pathogenic according to our data. Variant chr5-136056781-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-136056781-G-A is described in Lovd as [Pathogenic]. Variant chr5-136056781-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBI	NM_000358.3	c.1664G>A	p.Arg555Gln	missense_variant	12/17	ENST00000442011.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBI	ENST00000442011.7	c.1664G>A	p.Arg555Gln	missense_variant	12/17	1	NM_000358.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461396 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thiel-Behnke corneal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 22, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TGFBI: PS2, PM2, PM5, PS4:Moderate, PP1, PS3:Supporting, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 30, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 555 of the TGFBI protein (p.Arg555Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TGFBI function (PMID: 21135107). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBI protein function. ClinVar contains an entry for this variant (Variation ID: 7867). This missense change has been observed in individuals with autosomal dominant corneal dystrophy (PMID: 22355247). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.018	A;A
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.12	N
REVEL	Uncertain	0.57
Sift	Benign	0.27	T
Sift4G	Benign	0.12	T
Polyphen		0.77	P
Vest4		0.72
MutPred		0.84		Loss of methylation at R555 (P = 0.0298);
MVP		0.91
MPC		0.082
ClinPred		0.83	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.68

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: rs121909209; hg19: chr5-135392470; COSMIC: COSV59350572; COSMIC: COSV59350572;