rs56105708

chr3-30671754-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003242.6(TGFBR2):c.571G>A(p.Val191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,614,196 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V191V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00068 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.22

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003921181).
• BP6: Variant 3-30671754-G-A is Benign according to our data. Variant chr3-30671754-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30671754-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.571G>A	p.Val191Ile	missense_variant	4/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.571G>A	p.Val191Ile	missense_variant	4/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.646G>A	p.Val216Ile	missense_variant	5/8	1
TGFBR2	ENST00000672866.1	n.2167G>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00156 AC: 392 AN: 251202 Hom.: 4 AF XY: 0.00147 AC XY: 200 AN XY: 135742

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0185

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000524 AC: 766 AN: 1461878 Hom.: 8 Cov.: 34 AF XY: 0.000580 AC XY: 422 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0130

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000975 Hom.: 1

Bravo AF: 0.000903

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 02, 2016	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2017	Variant summary: The TGFBR2 c.571G>A (p.Val191Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 196 of 121384 control chromosomes (2 homozygotes) of all ethnicities sampled in ExAC, but was predominantly observed in the East Asian subpopulation at a frequency of 0.018741 (162/8644; 2 homozygotes). This frequency is about 5997 times the estimated maximal expected allele frequency of a pathogenic TGFBR2 variant (0.0000031), strongly suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant is referred to as a polymorphism in the literature and has been used as a SNP in an association study. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2013

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. -

Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2022

- -

Loeys-Dietz syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.044
Sift	Benign	0.45	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0010	B;.
Vest4		0.060
MVP		0.19
MPC		0.43
ClinPred		0.012	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.23

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: rs56105708; hg19: chr3-30713246; COSMIC: COSV55448710;