rs767581059

chr3-30671694-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003242.6(TGFBR2):c.511A>G(p.Ser171Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.48

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.511A>G	p.Ser171Gly	missense_variant	4/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.511A>G	p.Ser171Gly	missense_variant	4/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.586A>G	p.Ser196Gly	missense_variant	5/8	1
TGFBR2	ENST00000672866.1	n.2107A>G		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251268 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

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: 0.00000684 AC: 10 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 171 of the TGFBR2 protein (p.Ser171Gly). This variant is present in population databases (rs767581059, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 477548). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) did not meet the statistical confidence thresholds required to predict the impact of this variant on TGFBR2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2020

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 477548; Landrum et al., 2016) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.23	B;.
Vest4		0.78
MutPred		0.55		Gain of sheet (P = 0.0221);.;
MVP		0.81
MPC		1.1
ClinPred		0.44	T
GERP RS		5.4
Varity_R		0.50
gMVP		0.39

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: rs767581059; hg19: chr3-30713186;