rs587782979

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_003242.6(TGFBR2):c.1382G>A(p.Cys461Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 10.0

Variant links:

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]

TGFBR2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.954

PP5

Variant 3-30674232-G-A is Pathogenic according to our data. Variant chr3-30674232-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.1382G>A	p.Cys461Tyr	missense_variant	Exon 5 of 7	ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFBR2	ENST00000295754.10 link	c.1382G>A	p.Cys461Tyr	missense_variant	Exon 5 of 7	1	NM_003242.6	ENSP00000295754.5	P37173-1
TGFBR2	ENST00000359013.4 link	c.1457G>A	p.Cys486Tyr	missense_variant	Exon 6 of 8	1		ENSP00000351905.4	P37173-2
TGFBR2	ENST00000672866.1 link	n.2978G>A		non_coding_transcript_exon_variant	Exon 5 of 7
TGFBR2	ENST00000673203.1 link	n.260G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Apr 02, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1382G>A (p.C461Y) alteration is located in exon 5 (coding exon 5) of the TGFBR2 gene. This alteration results from a G to A substitution at nucleotide position 1382, causing the cysteine (C) at amino acid position 461 to be replaced by a tyrosine (Y). Based on data from the Genome Aggregation Database (gnomAD), the TGFBR2 c.1382G>A alteration was not observed, with coverage at this position. This alteration has been previously reported in individuals with Loeys-Dietz syndrome type I (Loeys, 2006). Using alternate nomenclature, this variant (p.C486Y, c.1457G>A) has also been reported de novo in a patient with an atrial septal defect (Jin, 2017). Another alteration affecting the same amino acid, p.C461R, was reported in a neonatal female patient with features consistent with Loeys-Dietz syndrome (Valenzuela, 2017). The p.C461 amino acid is conserved in available vertebrate species. The p.C461Y alteration is located in the kinase domain of TGFBR2. Based on internal structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Tebben, 2016; Zimmermann, 2017). Functional analysis in fibroblasts explanted from a patient with the p.C461Y alteration showed disruption of fibroblast transformation into myofibroblasts with TGF-B1 stimulation; however, the clinical relevance of those results is unclear (Inamoto, 2010). The in silico prediction for the p.C461Y alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Loeys-Dietz syndrome

Pathogenic:1

Nov 26, 2013

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Loeys-Dietz syndrome 2

Pathogenic:1

Sep 01, 2022

3billion, Medical Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000155839 / PMID: 16928994). A different missense change at the same codon (p.Cys461Arg) has been reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000393299 / PMID: 28344185). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.025

MutationAssessor

Benign

1.5

L;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-11

D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

D;.

Vest4

0.95

MutPred

0.81

Gain of catalytic residue at T458 (P = 0.1562);.;

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over