3-30672245-C-T

Position:

• chr3-30672245-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003242.6(TGFBR2):​c.1062C>T​(p.Leu354Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,604,244 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (34 hom.)
• Consequence: TGFBR2 NM_003242.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.192

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-30672245-C-T is Benign according to our data. Variant chr3-30672245-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672245-C-T is described in Lovd as [Benign]. Variant chr3-30672245-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BS2: High AC in GnomAd4 at 362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1062C>T	p.Leu354Leu	synonymous_variant	4/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1062C>T	p.Leu354Leu	synonymous_variant	4/7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.1137C>T	p.Leu379Leu	synonymous_variant	5/8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.2658C>T		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 363 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00376 AC: 922 AN: 245216 Hom.: 10 AF XY: 0.00470 AC XY: 621 AN XY: 132152

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0151

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00359 AC: 5206 AN: 1451916 Hom.: 34 Cov.: 34 AF XY: 0.00403 AC XY: 2908 AN XY: 720770

Gnomad4 AFR exome AF: 0.000421

Gnomad4 AMR exome AF: 0.00214

Gnomad4 ASJ exome AF: 0.0000787

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.000264

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74486

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00233

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2015	p.Leu354Leu in exon 4 of TGFBR2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1.6% (236/14206) of South Asian chromosomes including 5 homozygotes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs113194608). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 10, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TGFBR2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Marfan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 29, 2022

- -

Loeys-Dietz syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2015

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.2
DANN	Benign	0.79

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: rs113194608; hg19: chr3-30713737;