Genetic Variant NM_004612.4:c.*69A>G (chr9-99149374-A-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004612.4(TGFBR1):c.*69A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,597,340 control chromosomes in the GnomAD database, including 27,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2285 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25401 hom. )

Consequence

TGFBR1
NM_004612.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.32

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 -16 ACMG points.

BP6

Variant 9-99149374-A-G is Benign according to our data. Variant chr9-99149374-A-G is described in ClinVar as [Benign]. Clinvar id is 364103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99149374-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.*69A>G		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.*69A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25572

AN:

151998

Hom.:

2276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.159

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.171

GnomAD4 exome

AF:

0.182

AC:

263723

AN:

1445224

Hom.:

25401

Cov.:

AF XY:

0.181

AC XY:

130455

AN XY:

719962

show subpopulations

Gnomad4 AFR exome

AF:

0.158

Gnomad4 AMR exome

AF:

0.0969

Gnomad4 ASJ exome

AF:

0.192

Gnomad4 EAS exome

AF:

0.0361

Gnomad4 SAS exome

AF:

0.120

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.199

Gnomad4 OTH exome

AF:

0.176

GnomAD4 genome

AF:

0.168

AC:

25611

AN:

152116

Hom.:

2285

Cov.:

AF XY:

0.162

AC XY:

12014

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.164

Gnomad4 AMR

AF:

0.135

Gnomad4 ASJ

AF:

0.190

Gnomad4 EAS

AF:

0.0139

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.199

Gnomad4 OTH

AF:

0.168

Alfa

AF:

0.178

Hom.:

2162

Bravo

AF:

0.166

Asia WGS

AF:

0.0690

AC:

243

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19004027, 27234654, 25502482) -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

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

- -

Loeys-Dietz syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Jul 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.89

CADD

Benign

1.2

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -5

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