5-136029105-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000358.3(TGFBI):c.50G>C(p.Gly17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,525,908 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

TGFBI
NM_000358.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.552

Publications

0 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 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

TGFBI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022079647).

BS2

High AC in GnomAd4 at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3 link	c.50G>C	p.Gly17Ala	missense_variant	Exon 1 of 17	ENST00000442011.7	NP_000349.1	Q15582A0A0S2Z4Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFBI	ENST00000442011.7 link	c.50G>C	p.Gly17Ala	missense_variant	Exon 1 of 17	1	NM_000358.3	ENSP00000416330.2	Q15582
TGFBI	ENST00000504185.5 link	n.118G>C		non_coding_transcript_exon_variant	Exon 1 of 5	4
TGFBI	ENST00000506699.5 link	n.115G>C		non_coding_transcript_exon_variant	Exon 1 of 17	2
TGFBI	ENST00000507018.5 link	n.-35G>C		upstream_gene_variant		5		ENSP00000421540.1	H0Y8M8

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000912

AC:

AN:

120578

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00229

Gnomad AMR exome

AF:

0.0000841

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000662

AC:

AN:

1373658

Hom.:

Cov.:

AF XY:

0.0000443

AC XY:

AN XY:

677928

show subpopulations

African (AFR)

AF:

0.00270

AC:

AN:

29660

American (AMR)

AF:

0.0000851

AC:

AN:

35234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24778

East Asian (EAS)

AF:

0.00

AC:

AN:

34610

South Asian (SAS)

AF:

0.00

AC:

AN:

78236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075578

Other (OTH)

AF:

0.000122

AC:

AN:

57426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152250

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41580

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000925

Hom.:

Bravo

AF:

0.000876

ExAC

AF:

0.0000924

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.50G>C (p.G17A) alteration is located in exon 1 (coding exon 1) of the TGFBI gene. This alteration results from a G to C substitution at nucleotide position 50, causing the glycine (G) at amino acid position 17 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TGFBI-related disorder

Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

PhyloP100

0.55

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.47

REVEL

Uncertain

0.32

Sift

Benign

0.51

Sift4G

Benign

0.51

Polyphen

0.0010

Vest4

0.22

MVP

0.73

MPC

0.24

ClinPred

0.0023

GERP RS

0.73

PromoterAI

-0.077

Neutral

(source)

Varity_R

0.037

gMVP

0.31

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

5-136029105-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over