5-136052974-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBA1

The NM_000358.3(TGFBI):c.981A>G(p.Val327Val) variant causes a synonymous change. The variant allele was found at a frequency of 0.294 in 1,613,748 control chromosomes in the GnomAD database, including 72,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10205 hom., cov: 33)

Exomes 𝑓: 0.29 ( 62504 hom. )

Consequence

TGFBI
NM_000358.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.79

Publications

33 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.244).

BP6

Variant 5-136052974-A-G is Benign according to our data. Variant chr5-136052974-A-G is described in ClinVar as Benign. ClinVar VariationId is 255940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3 link	c.981A>G	p.Val327Val	synonymous_variant	Exon 8 of 17	ENST00000442011.7	NP_000349.1	Q15582A0A0S2Z4Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7 link	c.981A>G	p.Val327Val	synonymous_variant	Exon 8 of 17	1	NM_000358.3	ENSP00000416330.2		Q15582
TGFBI	ENST00000508767.5 link	c.239-44A>G		intron_variant	Intron 2 of 4	3		ENSP00000423871.1		H0Y9D7

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53240

AN:

152026

Hom.:

10188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.515

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.302

Gnomad EAS

AF:

0.333

Gnomad SAS

AF:

0.372

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.350

GnomAD2 exomes

AF:

0.318

AC:

79241

AN:

249006

AF XY:

0.314

show subpopulations

Gnomad AFR exome

AF:

0.518

Gnomad AMR exome

AF:

0.375

Gnomad ASJ exome

AF:

0.285

Gnomad EAS exome

AF:

0.322

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.288

AC:

420650

AN:

1461604

Hom.:

62504

Cov.:

AF XY:

0.289

AC XY:

209986

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.526

AC:

17619

AN:

33480

American (AMR)

AF:

0.370

AC:

16554

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

7464

AN:

26136

East Asian (EAS)

AF:

0.337

AC:

13377

AN:

39698

South Asian (SAS)

AF:

0.369

AC:

31848

AN:

86252

European-Finnish (FIN)

AF:

0.286

AC:

15279

AN:

53394

Middle Eastern (MID)

AF:

0.254

AC:

1466

AN:

5768

European-Non Finnish (NFE)

AF:

0.269

AC:

298664

AN:

1111800

Other (OTH)

AF:

0.304

AC:

18379

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

17593

35186

52780

70373

87966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10258

20516

30774

41032

51290

<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:

0.350

AC:

53319

AN:

152144

Hom.:

10205

Cov.:

AF XY:

0.350

AC XY:

26030

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.515

AC:

21363

AN:

41504

American (AMR)

AF:

0.319

AC:

4884

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

1047

AN:

3468

East Asian (EAS)

AF:

0.333

AC:

1723

AN:

5172

South Asian (SAS)

AF:

0.372

AC:

1791

AN:

4814

European-Finnish (FIN)

AF:

0.290

AC:

3077

AN:

10596

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.271

AC:

18399

AN:

67978

Other (OTH)

AF:

0.349

AC:

737

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1744

3488

5233

6977

8721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.310

Hom.:

5363

Bravo

AF:

0.360

Asia WGS

AF:

0.365

AC:

1267

AN:

3478

EpiCase

AF:

0.255

EpiControl

AF:

0.257

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 21, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Corneal dystrophy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.5

(source)

DANN

Benign

0.67

PhyloP100

5.8

Mutation Taster

=65/35

polymorphism (auto)

(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

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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