9-99128964-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_004612.4(TGFBR1):c.207C>T(p.Ser69=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.738

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-99128964-C-T is Benign according to our data. Variant chr9-99128964-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213865.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}. Variant chr9-99128964-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.738 with no splicing effect.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4	c.207C>T	p.Ser69=	synonymous_variant	2/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.207C>T	p.Ser69=	synonymous_variant	2/9	1	NM_004612.4	P4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 250878 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000268

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	In-silico analysis 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; Reported as likely benign by other clinical laboratories in ClinVar but additional evidence is not available (ClinVar Variant ID# 213865; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23142374) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 28, 2022	The TGFBR1 c.207C>T; p.Ser69= variant (rs145033378) is reported in the literature in an individual referred for genetic testing for thoracic aortic aneurysms and dissections, though its clinical significance was not demonstrated (Kathiravel 2013). This variant is also reported in ClinVar (Variation ID: 213865) and found in the Latino population with an overall allele frequency of 0.0565% (20/35368 alleles) in the Genome Aggregation Database. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. However, RNA sequencing studies would be required to confirm an effect on splicing. Due to limited information, the clinical significance of the p.Ser69= variant is uncertain at this time. References: Kathiravel U et al. High-density oligonucleotide-based resequencing assay for mutations causing syndromic and non-syndromic forms of thoracic aortic aneurysms and dissections. Mol Cell Probes. 2013;27(2):103-108. PMID: 23142374. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TGFBR1: BP4, BP7 -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2019	This alteration is classified as likely 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. -

Loeys-Dietz syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

- -

TGFBR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145033378; hg19: chr9-101891246;