rs121909217

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000358.3(TGFBI):c.1998G>C(p.Arg666Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,567,842 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

TGFBI
NM_000358.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:2

Conservation

PhyloP100: -0.483

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

epithelial-stromal TGFBI dystrophy
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia
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: G2P, Orphanet
Thiel-Behnke corneal dystrophy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
epithelial basement membrane dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TGFBI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059023798).

BP6

Variant 5-136062674-G-C is Benign according to our data. Variant chr5-136062674-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7878.

BS2

High AC in GnomAd4 at 157 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	NM_000358.3	MANE Select	c.1998G>C	p.Arg666Ser	missense	Exon 16 of 17	NP_000349.1	Q15582

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBI	ENST00000442011.7	TSL:1 MANE Select	c.1998G>C	p.Arg666Ser	missense	Exon 16 of 17	ENSP00000416330.2	Q15582
TGFBI	ENST00000508076.5	TSL:2	c.144G>C	p.Arg48Ser	missense	Exon 5 of 6	ENSP00000423935.1	D6RBX4
TGFBI	ENST00000514554.5	TSL:5	c.1058-512G>C		intron	N/A	ENSP00000421440.1	H0Y8L3

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00119

AC:

217

AN:

182164

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000896

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.00142

AC:

2015

AN:

1415554

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

961

AN XY:

699552

show subpopulations

African (AFR)

AF:

0.000276

AC:

AN:

32560

American (AMR)

AF:

0.00176

AC:

AN:

38134

Ashkenazi Jewish (ASJ)

AF:

0.0000787

AC:

AN:

25406

East Asian (EAS)

AF:

0.00

AC:

AN:

37688

South Asian (SAS)

AF:

0.00

AC:

AN:

80324

European-Finnish (FIN)

AF:

0.000930

AC:

AN:

50514

Middle Eastern (MID)

AF:

0.000704

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00166

AC:

1807

AN:

1086558

Other (OTH)

AF:

0.00135

AC:

AN:

58692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

114

229

343

458

572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152288

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41552

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.000861

AC:

102

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Corneal dystrophy (1)

Epithelial basement membrane dystrophy (1)

not specified (1)

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.29

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.73

M_CAP

Benign

0.042

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.0

PhyloP100

-0.48

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.49

REVEL

Uncertain

0.46

Sift

Benign

0.45

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.20

MutPred

0.80

Loss of helix (P = 0.028)

MVP

0.82

MPC

0.047

ClinPred

0.017

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.78

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over