Genetic Variant TGFBR1:c.*4489T>C (chr9-99153794-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004612.4(TGFBR1):c.*4489T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 206,986 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 466 hom., cov: 33)

Exomes 𝑓: 0.066 ( 153 hom. )

Consequence

TGFBR1
NM_004612.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.28

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 9-99153794-T-C is Benign according to our data. Variant chr9-99153794-T-C is described in ClinVar as [Benign]. Clinvar id is 364185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.*4489T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000374994.9	NP_004603.1	P36897-1Q5T7S2B4DXN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 link	c.*4489T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.0709

AC:

10794

AN:

152202

Hom.:

467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.0547

Gnomad ASJ

AF:

0.0726

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0841

Gnomad OTH

AF:

0.0783

GnomAD4 exome

AF:

0.0658

AC:

3596

AN:

54666

Hom.:

153

Cov.:

AF XY:

0.0687

AC XY:

1751

AN XY:

25470

show subpopulations

Gnomad4 AFR exome

AF:

0.0560

Gnomad4 AMR exome

AF:

0.0457

Gnomad4 ASJ exome

AF:

0.0629

Gnomad4 EAS exome

AF:

0.00247

Gnomad4 SAS exome

AF:

0.0415

Gnomad4 FIN exome

AF:

0.139

Gnomad4 NFE exome

AF:

0.0830

Gnomad4 OTH exome

AF:

0.0722

GnomAD4 genome

AF:

0.0709

AC:

10799

AN:

152320

Hom.:

466

Cov.:

AF XY:

0.0714

AC XY:

5321

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0549

Gnomad4 AMR

AF:

0.0546

Gnomad4 ASJ

AF:

0.0726

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0360

Gnomad4 FIN

AF:

0.119

Gnomad4 NFE

AF:

0.0841

Gnomad4 OTH

AF:

0.0775

Alfa

AF:

0.0765

Hom.:

706

Bravo

AF:

0.0665

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.28

DANN

Benign

0.37

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