chr5-136063763-T-G

Variant names:

• chr5-136063763-T-G
• rs4572
• NM_000358.3:c.*537T>G

Variant summary

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

The NM_000358.3(TGFBI):​c.*537T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 158,964 control chromosomes in the GnomAD database, including 9,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9025 hom., cov: 32)
  • Exomes 𝑓: 0.31 (416 hom.)
• Consequence: TGFBI NM_000358.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.489
• Publications: 21 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

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.*537T>G		3_prime_UTR	Exon 17 of 17	NP_000349.1	Q15582

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	ENST00000442011.7	TSL:1 MANE Select	c.*537T>G		3_prime_UTR	Exon 17 of 17	ENSP00000416330.2	Q15582
	TGFBI	ENST00000514554.5	TSL:5	c.*537T>G		3_prime_UTR	Exon 9 of 9	ENSP00000421440.1	H0Y8L3
	TGFBI	ENST00000508076.5	TSL:2	c.*537T>G		3_prime_UTR	Exon 6 of 6	ENSP00000423935.1	D6RBX4

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51517 AN: 151904 Hom.: 9018 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.341

GnomAD4 exome AF: 0.314 AC: 2181 AN: 6942 Hom.: 416 Cov.: 0 AF XY: 0.317 AC XY: 1174 AN XY: 3706

African (AFR) AF: 0.459 AC: 34 AN: 74

American (AMR) AF: 0.247 AC: 241 AN: 976

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 44 AN: 116

East Asian (EAS) AF: 0.422 AC: 108 AN: 256

South Asian (SAS) AF: 0.441 AC: 209 AN: 474

European-Finnish (FIN) AF: 0.303 AC: 165 AN: 544

Middle Eastern (MID) AF: 0.429 AC: 6 AN: 14

European-Non Finnish (NFE) AF: 0.305 AC: 1265 AN: 4146

Other (OTH) AF: 0.319 AC: 109 AN: 342

GnomAD4 genome AF: 0.339 AC: 51564 AN: 152022 Hom.: 9025 Cov.: 32 AF XY: 0.338 AC XY: 25112 AN XY: 74310

African (AFR) AF: 0.418 AC: 17340 AN: 41456

American (AMR) AF: 0.264 AC: 4041 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1175 AN: 3464

East Asian (EAS) AF: 0.376 AC: 1937 AN: 5150

South Asian (SAS) AF: 0.445 AC: 2149 AN: 4824

European-Finnish (FIN) AF: 0.299 AC: 3157 AN: 10554

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20713 AN: 67980

Other (OTH) AF: 0.341 AC: 721 AN: 2112

Alfa AF: 0.321 Hom.: 5272

Bravo AF: 0.339

Asia WGS AF: 0.400 AC: 1386 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Corneal dystrophy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.1
DANN	Benign	0.58
PhyloP100		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4572; hg19: chr5-135399452; COSMIC: COSV59354756; COSMIC: COSV59354756;