rs1553303217

chr1-218436130-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_003238.6(TGFB2):c.915T>A(p.Asp305Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.444

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003238.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35419035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.915T>A	p.Asp305Glu	missense_variant	5/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.999T>A	p.Asp333Glu	missense_variant	6/8
TGFB2	NR_138148.2	n.2166T>A		non_coding_transcript_exon_variant	5/7
TGFB2	NR_138149.2	n.2250T>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.915T>A	p.Asp305Glu	missense_variant	5/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.999T>A	p.Asp333Glu	missense_variant	6/8	1
TGFB2	ENST00000479322.1	n.399T>A		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 28, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFB2-related disease. This sequence change replaces aspartic acid with glutamic acid at codon 305 of the TGFB2 protein (p.Asp305Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.37
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.057	T;T
Polyphen		0.72	P;D
Vest4		0.47
MutPred		0.46		Gain of loop (P = 0.0851);.;
MVP		0.66
MPC		0.78
ClinPred		0.96	D
GERP RS		-1.5
Varity_R		0.42
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553303217; hg19: chr1-218609472;