9-99152591-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004612.4(TGFBR1):c.*3286G>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 0.162 in 228,664 control chromosomes in the GnomAD database, including 3,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2071 hom., cov: 32)

Exomes 𝑓: 0.17 ( 1177 hom. )

Consequence

TGFBR1
NM_004612.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.462

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Loeys-Dietz syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Loeys-Dietz syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
multiple self-healing squamous epithelioma
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 9-99152591-G-C is Benign according to our data. Variant chr9-99152591-G-C is described in ClinVar as Benign. ClinVar VariationId is 364164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004612.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TGFBR1	NM_004612.4	MANE Select	c.*3286G>C	3_prime_UTR	Exon 9 of 9	NP_004603.1
TGFBR1	NR_176360.1		n.4902G>C	non_coding_transcript_exon	Exon 9 of 9
TGFBR1	NR_176361.1		n.5007G>C	non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.*3286G>C	3_prime_UTR	Exon 9 of 9	ENSP00000364133.4
TGFBR1	ENST00000552516.5	TSL:1	c.*3286G>C	3_prime_UTR	Exon 9 of 9	ENSP00000447297.1
TGFBR1	ENST00000374990.6	TSL:1	c.*3286G>C	3_prime_UTR	Exon 8 of 8	ENSP00000364129.2

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

24073

AN:

152046

Hom.:

2073

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.0138

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.163

GnomAD4 exome

AF:

0.168

AC:

12877

AN:

76500

Hom.:

1177

Cov.:

AF XY:

0.170

AC XY:

5997

AN XY:

35374

show subpopulations

African (AFR)

AF:

0.118

AC:

434

AN:

3664

American (AMR)

AF:

0.119

AC:

281

AN:

2360

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

878

AN:

4798

East Asian (EAS)

AF:

0.0588

AC:

642

AN:

10914

South Asian (SAS)

AF:

0.135

AC:

AN:

650

European-Finnish (FIN)

AF:

0.175

AC:

AN:

302

Middle Eastern (MID)

AF:

0.141

AC:

AN:

468

European-Non Finnish (NFE)

AF:

0.198

AC:

9293

AN:

46972

Other (OTH)

AF:

0.179

AC:

1142

AN:

6372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

525

1051

1576

2102

2627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.158

AC:

24079

AN:

152164

Hom.:

2071

Cov.:

AF XY:

0.152

AC XY:

11276

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.129

AC:

5365

AN:

41526

American (AMR)

AF:

0.131

AC:

2006

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

661

AN:

3470

East Asian (EAS)

AF:

0.0141

AC:

AN:

5194

South Asian (SAS)

AF:

0.104

AC:

504

AN:

4824

European-Finnish (FIN)

AF:

0.131

AC:

1385

AN:

10590

Middle Eastern (MID)

AF:

0.154

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.199

AC:

13555

AN:

67958

Other (OTH)

AF:

0.161

AC:

340

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1049

2098

3146

4195

5244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.183

Hom.:

348

Bravo

AF:

0.155

Asia WGS

AF:

0.0640

AC:

224

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.0

(source)

DANN

Benign

0.65

PhyloP100

0.46

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over