chr3-30674123-A-C

Position:

• chr3-30674123-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_003242.6(TGFBR2):​c.1273A>C​(p.Met425Leu) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Protein kinase (size 300) in uniprot entity TGFR2_HUMAN there are 34 pathogenic changes around while only 5 benign (87%) in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 3-30674123-A-C is Pathogenic according to our data. Variant chr3-30674123-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573021.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1273A>C	p.Met425Leu	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.1273A>C	p.Met425Leu	missense_variant	5/7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.1348A>C	p.Met450Leu	missense_variant	6/8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.2869A>C		non_coding_transcript_exon_variant	5/7
TGFBR2	ENST00000673203.1	n.151A>C		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This variant disrupts the p.Met425 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16251899, 18781618; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 573021). This missense change has been observed in individuals with TGFBR2-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 425 of the TGFBR2 protein (p.Met425Leu). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 24, 2020

Variant summary: TGFBR2 c.1273A>C (p.Met425Leu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1273A>C in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Other missense variants affecting the same residue (e.g. M425V, M425I) or neighboring amino acids (e.g. Y424D, Y424H, A426T, P427L, P427S) were reported in affected individuals (HGMD), indicating that this protein region might be important for protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.92		Gain of glycosylation at Y424 (P = 0.0267);.;
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
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: rs104893817; hg19: chr3-30715615;