rs863223854

Variant names:

• chr3-30691459-G-A
• rs863223854
• NM_003242.6:c.1564G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-30691459-G-A
• chr3-30691459-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1564G>A​(p.Asp522Asn) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• 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 14 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with CLU (size 128) in uniprot entity TGFR2_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 3-30691459-G-A is Pathogenic according to our data. Variant chr3-30691459-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30691459-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1564G>A	p.Asp522Asn	missense_variant	Exon 7 of 7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1564G>A	p.Asp522Asn	missense_variant	Exon 7 of 7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Jul 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 522 of the TGFBR2 protein (p.Asp522Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TGFBR2-related conditions (PMID: 17599521, 30675029, 34422331; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as NM_001024847.2:c.1639G>A (p.Asp547Asn). ClinVar contains an entry for this variant (Variation ID: 213936). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR2 protein function. This variant disrupts the p.Asp522 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. -

Nov 20, 2018

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 06, 2017

GeneDx

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The D522N variant of uncertain significance in the TGFBR2 gene has been reported in an individual with a clinical diagnosis of Loeys Dietz syndrome (LDS) and classic features (Lee et al., 2007); however, segregation information was not provided. This variant is not observed in large population cohorts (Lek et al., 2016). The D522N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the D522N variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Finally, while missense variants in nearby residues (G520R, G520F, G520Y, W521R, D524N, D524Y) have been reported in HGMD in association with TGFBR2-related disorders (Stenson et al., 2014); the pathogenicity of these variants has not been definitively determined. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.79		Gain of loop (P = 0.2045);.;
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.86

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: rs863223854; hg19: chr3-30732951; COSMIC: COSV55443169;