rs375330013

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003242.6(TGFBR2):c.95-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

TGFBR2
NM_003242.6 splice_region, intron

Scores

Splicing: ADA: 0.4685

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: -0.126

Variant links:

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 links:

TGFBR2 (HGNC:):

TGFBR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6 linkuse as main transcript	c.95-3C>A		splice_region_variant, intron_variant		ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
TGFBR2	ENST00000295754.10 linkuse as main transcript	c.95-3C>A	splice_region_variant, intron_variant	1	NM_003242.6	ENSP00000295754.5	P37173-1
TGFBR2	ENST00000359013.4 linkuse as main transcript	c.170-3C>A	splice_region_variant, intron_variant	1		ENSP00000351905.4	P37173-2
TGFBR2	ENST00000672866.1 linkuse as main transcript	n.1691-3C>A	splice_region_variant, intron_variant
TGFBR2	ENST00000673250.1 linkuse as main transcript	n.219-3C>A	splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250744

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135526

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461628

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727124

show subpopulations

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:

0.0000693

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2023	This variant is located close to intron 2 canonical splice acceptor site of the TGFBR2 gene. Splice prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual referred for aortopathy testing (PMID: 25944730). This variant has been identified in 6/282146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2020	The c.95-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the TGFBR2 gene. This alteration has been reported in a cohort of individuals referred for aortopathy panel genetic testing, but clinical details were limited (Wooderchak-Donahue W et al. Am. J. Med. Genet. A. 2015;167A:1747-57). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change falls in intron 1 of the TGFBR2 gene. It does not directly change the encoded amino acid sequence of the TGFBR2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs375330013, gnomAD 0.005%). This variant has been observed in individual(s) with aortopathy (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 408434). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

Loeys-Dietz syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are mechanisms of disease in this gene and are associated with Loeys-Dietz syndrome 2 (MIM#610168). Both LoF and GoF have been demonstrated as potential disease mechanisms in patients with Loeys-Dietz syndrome 2 (GeneReview, PMID: 15731757, 32528524, 28679693). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0710 - Other variants affecting the same nucleotide comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.95-3C>G and c.95-3C>T have both been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been regarded as a VUS both in ClinVar and in an individual with a suspected aortopathy (PMID: 25944730). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2020

Identified in one individual referred for aortopathy genetic testing in the published literature (Wooderchak-Donahue et al., 2015); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25944730) -

Diabetic retinopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs375330013 with diabetic retinopathy. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.3

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.47

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over