rs727504421

chr3-30691465-G-Achr3-30691465-G-Cchr3-30691465-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003242.6(TGFBR2):c.1570G>A(p.Asp524Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D524Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 3-30691465-G-A is Pathogenic according to our data. Variant chr3-30691465-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1570G>A	p.Asp524Asn	missense_variant	7/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1570G>A	p.Asp524Asn	missense_variant	7/7	1	NM_003242.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17470566, 27879313, 30158670, 16928994) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TGFBR2: PM1, PM2, PM5, PP3, PP4, PS4:Supporting -

Marfan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 524 of the TGFBR2 protein (p.Asp524Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 16928994, 17470566, 30158670; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 180541). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Loeys-Dietz syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 25, 2014

- -

Loeys-Dietz syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Oct 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;T
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.90		Loss of disorder (P = 0.246);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.81
gMVP		0.85

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: rs727504421; hg19: chr3-30732957; COSMIC: COSV55448438;