rs2072239

Variant names:

• chr5-136056818-G-A
• rs2072239
• NM_000358.3:c.1678+23G>A

Variant summary

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

The NM_000358.3(TGFBI):​c.1678+23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,597,300 control chromosomes in the GnomAD database, including 48,380 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 0.19 (3378 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45002 hom.)
• Consequence: TGFBI NM_000358.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 16 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.1678+23G>A		intron_variant	Intron 12 of 16	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.1678+23G>A		intron_variant	Intron 12 of 16	1	NM_000358.3	ENSP00000416330.2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28633 AN: 151760 Hom.: 3380 Cov.: 31

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.252 AC: 56330 AN: 223496 AF XY: 0.257

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.245 AC: 354324 AN: 1445422 Hom.: 45002 Cov.: 32 AF XY: 0.248 AC XY: 177711 AN XY: 717626

African (AFR) AF: 0.0378 AC: 1245 AN: 32958

American (AMR) AF: 0.322 AC: 13414 AN: 41654

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5053 AN: 25744

East Asian (EAS) AF: 0.210 AC: 8201 AN: 39116

South Asian (SAS) AF: 0.337 AC: 28543 AN: 84792

European-Finnish (FIN) AF: 0.255 AC: 13440 AN: 52764

Middle Eastern (MID) AF: 0.166 AC: 948 AN: 5704

European-Non Finnish (NFE) AF: 0.244 AC: 269622 AN: 1102944

Other (OTH) AF: 0.232 AC: 13858 AN: 59746

GnomAD4 genome AF: 0.189 AC: 28642 AN: 151878 Hom.: 3378 Cov.: 31 AF XY: 0.191 AC XY: 14193 AN XY: 74198

African (AFR) AF: 0.0441 AC: 1828 AN: 41440

American (AMR) AF: 0.242 AC: 3691 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 696 AN: 3472

East Asian (EAS) AF: 0.196 AC: 1007 AN: 5150

South Asian (SAS) AF: 0.336 AC: 1599 AN: 4758

European-Finnish (FIN) AF: 0.260 AC: 2741 AN: 10526

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16464 AN: 67958

Other (OTH) AF: 0.201 AC: 421 AN: 2098

Alfa AF: 0.221 Hom.: 1502

Bravo AF: 0.180

Asia WGS AF: 0.242 AC: 841 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.045
DANN	Benign	0.54
PhyloP100		-1.4
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: rs2072239; hg19: chr5-135392507; COSMIC: COSV59353895; COSMIC: COSV59353895;