Variant 5-136029169-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000358.3(TGFBI):c.114G>C(p.Arg38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TGFBI
NM_000358.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0500

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBI	NM_000358.3 linkuse as main transcript	c.114G>C	p.Arg38Ser	missense_variant	1/17	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TGFBI	ENST00000442011.7 linkuse as main transcript	c.114G>C	p.Arg38Ser	missense_variant	1/17	1	NM_000358.3	ENSP00000416330	P1
TGFBI	ENST00000504185.5 linkuse as main transcript	n.182G>C		non_coding_transcript_exon_variant	1/5	4
TGFBI	ENST00000506699.5 linkuse as main transcript	n.179G>C		non_coding_transcript_exon_variant	1/17	2
TGFBI	ENST00000507018.5 linkuse as main transcript	c.33G>C	p.Arg11Ser	missense_variant, NMD_transcript_variant	1/17	5		ENSP00000421540

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.35e-7

AC:

AN:

1360634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.114G>C (p.R38S) alteration is located in exon 1 (coding exon 1) of the TGFBI gene. This alteration results from a G to C substitution at nucleotide position 114, causing the arginine (R) at amino acid position 38 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.54

MutPred

0.60

Loss of MoRF binding (P = 0.0218);

MVP

0.97

MPC

0.053

ClinPred

0.99

GERP RS

1.6

Varity_R

0.85

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over