rs1060501983

chr3-30672429-A-Gchr3-30672429-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003242.6(TGFBR2):c.1246A>G(p.Ser416Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S416T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1246A>G	p.Ser416Gly	missense_variant	4/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1246A>G	p.Ser416Gly	missense_variant	4/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.1321A>G	p.Ser441Gly	missense_variant	5/8	1
TGFBR2	ENST00000672866.1	n.2842A>G		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 26, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function and splicing. It has been classified as a Variant of Uncertain Significance. 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 disruptive, but these predictions have not been confirmed by published functional studies. Furthermore, algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFBR2-related disease. This sequence change replaces serine with glycine at codon 416 of the TGFBR2 protein (p.Ser416Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.31	T;T
Sift4G	Benign	0.10	T;T
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.36		Loss of stability (P = 0.0601);.;
MVP		0.96
MPC		1.4
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.78

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: rs1060501983; hg19: chr3-30713921;