rs397516837

Variant names:

• chr3-30644770-G-A
• rs397516837
• NM_003242.6:c.118G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003242.6(TGFBR2):​c.118G>A​(p.Asp40Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16273853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.118G>A	p.Asp40Asn	missense_variant	Exon 2 of 7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.118G>A	p.Asp40Asn	missense_variant	Exon 2 of 7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.193G>A	p.Asp65Asn	missense_variant	Exon 3 of 8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.1714G>A		non_coding_transcript_exon_variant	Exon 2 of 7
TGFBR2	ENST00000673250.1	n.242G>A		non_coding_transcript_exon_variant	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Asp40Asn varian t in TGFBR2 has not been reported in the literature or identified in our laborat ory in over 380 individuals. This residue is not highly conserved and computatio nal analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of im pact to the normal function of the protein. It should be noted that the sensitiv ity and specificity of these computational programs has not been determined by o ur laboratory. Therefore, the clinical significance of this variant cannot be de termined at this time. The clinical significance of this variant should be inter preted in the context of this individual's clinical manifestations. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.69	N;N
REVEL	Benign	0.20
Sift	Benign	0.14	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;.
Vest4		0.28
MutPred		0.32		Loss of sheet (P = 0.1158);.;
MVP		0.93
MPC		0.52
ClinPred		0.33	T
GERP RS		5.7
Varity_R		0.096
gMVP		0.42

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: rs397516837; hg19: chr3-30686262;