chr5-136029105-G-T

Variant names:

• chr5-136029105-G-T
• rs770699457
• NM_000358.3:c.50G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000358.3(TGFBI):​c.50G>T​(p.Gly17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,373,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TGFBI NM_000358.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12150678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.50G>T	p.Gly17Val	missense_variant	Exon 1 of 17	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.50G>T	p.Gly17Val	missense_variant	Exon 1 of 17	1	NM_000358.3	ENSP00000416330.2
TGFBI	ENST00000504185.5	n.118G>T		non_coding_transcript_exon_variant	Exon 1 of 5	4
TGFBI	ENST00000506699.5	n.115G>T		non_coding_transcript_exon_variant	Exon 1 of 17	2
TGFBI	ENST00000507018.5	n.-35G>T		upstream_gene_variant		5		ENSP00000421540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000829 AC: 1 AN: 120578 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1373658 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 677928

African (AFR) AF: 0.00 AC: 0 AN: 29660

American (AMR) AF: 0.00 AC: 0 AN: 35234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24778

East Asian (EAS) AF: 0.00 AC: 0 AN: 34610

South Asian (SAS) AF: 0.0000256 AC: 2 AN: 78236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075578

Other (OTH) AF: 0.00 AC: 0 AN: 57426

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000185 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.55
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.91	N
REVEL	Uncertain	0.30
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.31
MVP		0.67
MPC		0.31
ClinPred		0.058	T
GERP RS		0.73
PromoterAI		-0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.30
Mutation Taster		=90/10	polymorphism

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: rs770699457; hg19: chr5-135364794;