rs587782979

Positions:

• chr3-30674232-G-A
• chr3-30674232-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000295754.10(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C461R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR2 ENST00000295754.10 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000295754.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-30674231-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 393299.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1382G>A	p.Cys461Tyr	missense_variant	5/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1382G>A	p.Cys461Tyr	missense_variant	5/7	1	NM_003242.6	ENSP00000295754	P1
TGFBR2	ENST00000359013.4	c.1457G>A	p.Cys486Tyr	missense_variant	6/8	1		ENSP00000351905
TGFBR2	ENST00000672866.1	n.2978G>A		non_coding_transcript_exon_variant	5/7
TGFBR2	ENST00000673203.1	n.260G>A		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2021

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

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 26, 2013

- -

Loeys-Dietz syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

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	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
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	D
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

Other links and lift over

dbSNP: rs587782979; hg19: chr3-30715724;