rs756463

Variant names:

• chr5-136032068-C-T
• rs756463
• NM_000358.3:c.135-1695C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000358.3(TGFBI):​c.135-1695C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,058 control chromosomes in the GnomAD database, including 7,521 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7521 hom., cov: 32)
• Consequence: TGFBI NM_000358.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0570
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.135-1695C>T		intron_variant	Intron 1 of 16	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.135-1695C>T		intron_variant	Intron 1 of 16	1	NM_000358.3	ENSP00000416330.2
TGFBI	ENST00000504185.5	n.203-1695C>T		intron_variant	Intron 1 of 4	4
TGFBI	ENST00000506699.5	n.200-1695C>T		intron_variant	Intron 1 of 16	2
TGFBI	ENST00000507018.5	n.51-1695C>T		intron_variant	Intron 1 of 16	5		ENSP00000421540.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46684 AN: 151940 Hom.: 7514 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.307 AC: 46726 AN: 152058 Hom.: 7521 Cov.: 32 AF XY: 0.306 AC XY: 22762 AN XY: 74326

African (AFR) AF: 0.400 AC: 16572 AN: 41456

American (AMR) AF: 0.368 AC: 5621 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3468

East Asian (EAS) AF: 0.372 AC: 1922 AN: 5164

South Asian (SAS) AF: 0.189 AC: 908 AN: 4814

European-Finnish (FIN) AF: 0.232 AC: 2456 AN: 10572

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.256 AC: 17412 AN: 67990

Other (OTH) AF: 0.304 AC: 642 AN: 2112

Alfa AF: 0.282 Hom.: 9589

Bravo AF: 0.323

Asia WGS AF: 0.315 AC: 1096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.33
PhyloP100		0.057
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs756463; hg19: chr5-135367757;