Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The ENST00000374994.9(TGFBR1):c.46G>A(p.Val16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,059,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TGFBR1
ENST00000374994.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.672

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15085885).

BP6

Variant 9-99105251-G-A is Benign according to our data. Variant chr9-99105251-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477556.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000498 (72/144538) while in subpopulation AFR AF = 0.00174 (70/40260). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374994.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TGFBR1	NM_004612.4	MANE Select	c.46G>A	p.Val16Met	missense	Exon 1 of 9	NP_004603.1
TGFBR1	NM_001407420.1		c.-298G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001394349.1
TGFBR1	NM_001407422.1		c.-267G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001394351.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.46G>A	p.Val16Met	missense	Exon 1 of 9	ENSP00000364133.4
TGFBR1	ENST00000552516.5	TSL:1	c.46G>A	p.Val16Met	missense	Exon 1 of 9	ENSP00000447297.1
TGFBR1	ENST00000374990.6	TSL:1	c.46G>A	p.Val16Met	missense	Exon 1 of 8	ENSP00000364129.2

Frequencies

GnomAD3 genomes

AF:

0.000498

AC:

AN:

144434

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

640

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000382

AC:

AN:

915134

Hom.:

Cov.:

AF XY:

0.0000256

AC XY:

AN XY:

430024

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

17786

American (AMR)

AF:

0.00

AC:

AN:

3124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7798

East Asian (EAS)

AF:

0.00

AC:

AN:

10154

South Asian (SAS)

AF:

0.00

AC:

AN:

18160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2036

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

817314

Other (OTH)

AF:

0.0000620

AC:

AN:

32246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000498

AC:

AN:

144538

Hom.:

Cov.:

AF XY:

0.000455

AC XY:

AN XY:

70342

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

40260

American (AMR)

AF:

0.000136

AC:

AN:

14688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

5000

South Asian (SAS)

AF:

0.00

AC:

AN:

4720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65046

Other (OTH)

AF:

0.00

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000356

Hom.:

Bravo

AF:

0.000570

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Familial thoracic aortic aneurysm and aortic dissection (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

PhyloP100

-0.67

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.29

REVEL

Benign

0.20

Sift

Benign

0.083

Sift4G

Benign

0.17

Polyphen

0.54

Vest4

0.11

MVP

0.53

MPC

0.52

ClinPred

0.072

GERP RS

-0.38

PromoterAI

0.00080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.067

gMVP

0.45

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1021523079

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over