rs121909211

chr5-136046407-G-Achr5-136046407-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PM1 PM5 PP5_Very_Strong BS2

The NM_000358.3(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 NM_000358.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.76

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_pathogenic. Variant got 8 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 NM_000358.3
• 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].
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBI	NM_000358.3	c.371G>A	p.Arg124His	missense_variant	4/17	ENST00000442011.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 32

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: 10 AN: 249054 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135110

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: 31 AN: 1461606 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727078

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: 5 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74444

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.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Avellino corneal dystrophy Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
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, 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	Invitae	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	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.55		Loss of phosphorylation at T125 (P = 0.1017);
MVP		0.98
MPC		0.33
ClinPred		0.44	T
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

Other links and lift over

dbSNP: rs121909211; hg19: chr5-135382096; COSMIC: COSV59350998; COSMIC: COSV59350998;