3-30672246-G-T

Variant names:

• chr3-30672246-G-T
• rs104893813
• NM_003242.6:c.1063G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1 PM2 PM5 PP2 BS2

The NM_003242.6(TGFBR2):​c.1063G>T​(p.Ala355Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,452,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A355P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Loeys-Dietz syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• Loeys-Dietz syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-30672246-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12509.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 91 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.2437 (below the threshold of 3.09). Trascript score misZ: 2.9378 (below the threshold of 3.09). GenCC associations: The gene is linked to Loeys-Dietz syndrome, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 2.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003242.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	NM_003242.6	MANE Select	c.1063G>T	p.Ala355Ser	missense	Exon 4 of 7	NP_003233.4
	TGFBR2	NM_001407126.1		c.1246G>T	p.Ala416Ser	missense	Exon 6 of 9	NP_001394055.1
	TGFBR2	NM_001407127.1		c.1171G>T	p.Ala391Ser	missense	Exon 5 of 8	NP_001394056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.1063G>T	p.Ala355Ser	missense	Exon 4 of 7	ENSP00000295754.5
	TGFBR2	ENST00000359013.4	TSL:1	c.1138G>T	p.Ala380Ser	missense	Exon 5 of 8	ENSP00000351905.4
	TGFBR2	ENST00000714391.1		c.1036G>T	p.Ala346Ser	missense	Exon 5 of 8	ENSP00000519658.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 245244 AF XY: 0.00000757

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452070 Hom.: 0 Cov.: 34 AF XY: 0.00000416 AC XY: 3 AN XY: 720850

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105600

Other (OTH) AF: 0.0000167 AC: 1 AN: 59970

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 2 Uncertain:1

May 04, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 355 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 2/245244 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ala355Pro, has been reported in individuals affected with Loeys-Dietz Syndrome or other TGFBR2-related conditions (PMID: 15731757, ClinVar SCV002305432.2), indicating that alanine at this position is important for TGFBR2 protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.65
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.87	P
Vest4		0.29
MVP		0.95
MPC		0.58
ClinPred		0.41	T
GERP RS		2.8
Varity_R		0.53
gMVP		0.69
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs104893813; hg19: chr3-30713738;