rs7861780

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004612.4(TGFBR1):c.1125A>C(p.Thr375=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,796 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts 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. T375T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 21 hom. )

Consequence

TGFBR1
NM_004612.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.587

Variant links:

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]

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 9-99144883-A-C is Benign according to our data. Variant chr9-99144883-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 36857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99144883-A-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.587 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00289 (441/152358) while in subpopulation SAS AF= 0.00435 (21/4830). AF 95% confidence interval is 0.00385. There are 3 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4 linkuse as main transcript	c.1125A>C	p.Thr375=	synonymous_variant	6/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9 linkuse as main transcript	c.1125A>C	p.Thr375=	synonymous_variant	6/9	1	NM_004612.4	P4	P36897-1

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

440

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00398

AC:

1000

AN:

251038

Hom.:

AF XY:

0.00405

AC XY:

550

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00420

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00395

Gnomad FIN exome

AF:

0.00181

Gnomad NFE exome

AF:

0.00545

Gnomad OTH exome

AF:

0.00590

GnomAD4 exome

AF:

0.00445

AC:

6503

AN:

1461438

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

3328

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00436

Gnomad4 ASJ exome

AF:

0.00237

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00437

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.00489

Gnomad4 OTH exome

AF:

0.00439

GnomAD4 genome

AF:

0.00289

AC:

441

AN:

152358

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00425

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.00320

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.00393

EpiControl

AF:

0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:6

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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 13, 2012	Thr375Thr in exon 6 of TGFBR1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and it has been identified in 0.4% (29/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs7861780). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TGFBR1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Loeys-Dietz syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Loeys-Dietz syndrome 1

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 22, 2022

- -

Multiple self-healing squamous epithelioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.1

DANN

Benign

0.83

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

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