5-136063763-T-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.*537T>G		3_prime_UTR_variant	Exon 17 of 17	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.*537T>G		3_prime_UTR_variant	Exon 17 of 17	1	NM_000358.3	ENSP00000416330.2

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

Gnomad4 AFR exome AF: 0.459

Gnomad4 AMR exome AF: 0.247

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.422

Gnomad4 SAS exome AF: 0.441

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.319

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

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.376

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.341

Alfa AF: 0.321 Hom.: 4864

Bravo AF: 0.339

Asia WGS AF: 0.400 AC: 1386 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.1
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs4572; hg19: chr5-135399452; COSMIC: COSV59354756; COSMIC: COSV59354756;