5-136046482-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_000358.3(TGFBI):c.446C>T(p.Ala149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 1,608,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: TGFBI NM_000358.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a domain FAS1 1 (size 133) in uniprot entity BGH3_HUMAN there are 37 pathogenic changes around while only 4 benign (90%) in NM_000358.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.3942694).
• BS2: High AC in GnomAdExome at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBI	NM_000358.3	c.446C>T	p.Ala149Val	missense_variant	4/17	ENST00000442011.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBI	ENST00000442011.7	c.446C>T	p.Ala149Val	missense_variant	4/17	1	NM_000358.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 25 AN: 241116 Hom.: 0 AF XY: 0.0000916 AC XY: 12 AN XY: 131016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000402

Gnomad SAS exome AF: 0.000302

Gnomad FIN exome AF: 0.000190

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000549 AC: 80 AN: 1456044 Hom.: 0 Cov.: 31 AF XY: 0.0000677 AC XY: 49 AN XY: 723460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000406

Gnomad4 SAS exome AF: 0.000327

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000993 AC: 12

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.446C>T (p.A149V) alteration is located in exon 4 (coding exon 4) of the TGFBI gene. This alteration results from a C to T substitution at nucleotide position 446, causing the alanine (A) at amino acid position 149 to be replaced by a valine (V). 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	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.62
Sift	Benign	0.054	T
Sift4G	Benign	0.25	T
Polyphen		0.95	P
Vest4		0.39
MutPred		0.53		Loss of disorder (P = 0.1683);
MVP		0.96
MPC		0.090
ClinPred		0.14	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76212104; hg19: chr5-135382171;