5-136029105-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000358.3(TGFBI):c.50G>C(p.Gly17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,525,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: TGFBI NM_000358.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.552

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022079647).
• BP6: Variant 5-136029105-G-C is Benign according to our data. Variant chr5-136029105-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2352977.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBI	NM_000358.3	c.50G>C	p.Gly17Ala	missense_variant	1/17	ENST00000442011.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBI	ENST00000442011.7	c.50G>C	p.Gly17Ala	missense_variant	1/17	1	NM_000358.3	P1
TGFBI	ENST00000504185.5	n.118G>C		non_coding_transcript_exon_variant	1/5	4
TGFBI	ENST00000506699.5	n.115G>C		non_coding_transcript_exon_variant	1/17	2
TGFBI	ENST00000507018.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000912 AC: 11 AN: 120578 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66572

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.0000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000662 AC: 91 AN: 1373658 Hom.: 0 Cov.: 31 AF XY: 0.0000443 AC XY: 30 AN XY: 677928

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.0000851

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.30e-7

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74426

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000925 Hom.: 0

Bravo AF: 0.000876

ExAC AF: 0.0000924 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.50G>C (p.G17A) 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 50, causing the glycine (G) at amino acid position 17 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TGFBI-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.58
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.47	N
REVEL	Uncertain	0.32
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.22
MVP		0.73
MPC		0.24
ClinPred		0.0023	T
GERP RS		0.73
Varity_R		0.037
gMVP		0.31

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: rs770699457; hg19: chr5-135364794;