5-136029203-C-A

Variant names:

• chr5-136029203-C-A
• rs529657143
• NM_000358.3:c.134+14C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000358.3(TGFBI):​c.134+14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,472,572 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (18 hom.)
• Consequence: TGFBI NM_000358.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0430
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 5-136029203-C-A is Benign according to our data. Variant chr5-136029203-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350866.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00285 (434/152294) while in subpopulation NFE AF = 0.00547 (372/68014). AF 95% confidence interval is 0.00501. There are 1 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 434 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.134+14C>A		intron_variant	Intron 1 of 16	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.134+14C>A		intron_variant	Intron 1 of 16	1	NM_000358.3	ENSP00000416330.2
TGFBI	ENST00000504185.5	n.202+14C>A		intron_variant	Intron 1 of 4	4
TGFBI	ENST00000506699.5	n.199+14C>A		intron_variant	Intron 1 of 16	2
TGFBI	ENST00000507018.5	n.50+14C>A		intron_variant	Intron 1 of 16	5		ENSP00000421540.1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00298 AC: 226 AN: 75720 AF XY: 0.00273

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.000804

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00137

Gnomad NFE exome AF: 0.00630

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00476 AC: 6291 AN: 1320278 Hom.: 18 Cov.: 30 AF XY: 0.00460 AC XY: 2976 AN XY: 646936

African (AFR) AF: 0.000598 AC: 16 AN: 26756

American (AMR) AF: 0.000904 AC: 26 AN: 28762

Ashkenazi Jewish (ASJ) AF: 0.0000896 AC: 2 AN: 22328

East Asian (EAS) AF: 0.00 AC: 0 AN: 31126

South Asian (SAS) AF: 0.00132 AC: 94 AN: 71162

European-Finnish (FIN) AF: 0.00213 AC: 69 AN: 32350

Middle Eastern (MID) AF: 0.000255 AC: 1 AN: 3928

European-Non Finnish (NFE) AF: 0.00560 AC: 5869 AN: 1048892

Other (OTH) AF: 0.00389 AC: 214 AN: 54974

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74460

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00203 Hom.: 2

Bravo AF: 0.00268

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Corneal dystrophy Uncertain:1

Jan 13, 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 Benign:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.043
PromoterAI		0.0044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs529657143; hg19: chr5-135364892;