5-136047741-A-G

Variant names:

• chr5-136047741-A-G
• rs2073510
• NM_000358.3:c.771+321A>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.771+321A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 298,946 control chromosomes in the GnomAD database, including 15,995 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 0.34 (9117 hom., cov: 33)
  • Exomes 𝑓: 0.30 (6878 hom.)
• Consequence: TGFBI NM_000358.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 2 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 (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.771+321A>G		intron_variant	Intron 6 of 16	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.771+321A>G		intron_variant	Intron 6 of 16	1	NM_000358.3	ENSP00000416330.2
TGFBI	ENST00000508767.5	c.96+321A>G		intron_variant	Intron 1 of 4	3		ENSP00000423871.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51081 AN: 151976 Hom.: 9103 Cov.: 33

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.299 AC: 43853 AN: 146852 Hom.: 6878 Cov.: 0 AF XY: 0.301 AC XY: 22487 AN XY: 74796

African (AFR) AF: 0.455 AC: 2576 AN: 5664

American (AMR) AF: 0.345 AC: 2254 AN: 6526

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1416 AN: 4802

East Asian (EAS) AF: 0.337 AC: 3195 AN: 9468

South Asian (SAS) AF: 0.368 AC: 4664 AN: 12680

European-Finnish (FIN) AF: 0.309 AC: 2252 AN: 7280

Middle Eastern (MID) AF: 0.271 AC: 189 AN: 698

European-Non Finnish (NFE) AF: 0.271 AC: 24565 AN: 90688

Other (OTH) AF: 0.303 AC: 2742 AN: 9046

GnomAD4 genome AF: 0.336 AC: 51147 AN: 152094 Hom.: 9117 Cov.: 33 AF XY: 0.337 AC XY: 25041 AN XY: 74362

African (AFR) AF: 0.460 AC: 19089 AN: 41476

American (AMR) AF: 0.312 AC: 4776 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1045 AN: 3468

East Asian (EAS) AF: 0.333 AC: 1717 AN: 5158

South Asian (SAS) AF: 0.373 AC: 1798 AN: 4820

European-Finnish (FIN) AF: 0.309 AC: 3276 AN: 10590

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18442 AN: 67978

Other (OTH) AF: 0.335 AC: 706 AN: 2108

Alfa AF: 0.328 Hom.: 1101

Bravo AF: 0.343

Asia WGS AF: 0.360 AC: 1250 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	0.023
DANN	Benign	0.62
PhyloP100		-1.5
PromoterAI		0.013	Neutral
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: rs2073510; hg19: chr5-135383430;