dbSNP rs56014374: TGFBR1:p.Val153Ile (chr9-99132622-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004612.4(TGFBR1):c.457G>A(p.Val153Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,614,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 3 hom. )

Consequence

TGFBR1
NM_004612.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 4.71

Publications

12 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, Unknown 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
multiple self-healing squamous epithelioma
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

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 (MetaRNN=0.013447493).

BP6

Variant 9-99132622-G-A is Benign according to our data. Variant chr9-99132622-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (174/152296) while in subpopulation NFE AF = 0.0021 (143/68030). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 174 AD,Unknown gene.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR1	NM_004612.4	MANE Select	c.457G>A	p.Val153Ile	missense	Exon 3 of 9	NP_004603.1	P36897-1
TGFBR1	NM_001306210.2		c.469G>A	p.Val157Ile	missense	Exon 3 of 9	NP_001293139.1	P36897-2
TGFBR1	NM_001407416.1		c.469G>A	p.Val157Ile	missense	Exon 3 of 8	NP_001394345.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.457G>A	p.Val153Ile	missense	Exon 3 of 9	ENSP00000364133.4	P36897-1
TGFBR1	ENST00000552516.5	TSL:1	c.469G>A	p.Val157Ile	missense	Exon 3 of 9	ENSP00000447297.1	P36897-2
TGFBR1	ENST00000374990.6	TSL:1	c.343+3522G>A		intron	N/A	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00103

AC:

259

AN:

251094

AF XY:

0.000958

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00169

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00201

AC:

2933

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

1384

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000648

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000487

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00241

AC:

2685

AN:

1111996

Other (OTH)

AF:

0.00177

AC:

107

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

196

391

587

782

978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

216

324

432

540

<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:

0.00114

AC:

174

AN:

152296

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41562

American (AMR)

AF:

0.000327

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00407

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00110

AC:

134

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial thoracic aortic aneurysm and aortic dissection (6)

not provided (6)

Loeys-Dietz syndrome (2)

Loeys-Dietz syndrome 1 (2)

Ehlers-Danlos syndrome (1)

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.025

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0083

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

PhyloP100

4.7

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.37

REVEL

Benign

0.091

Sift

Benign

0.36

Sift4G

Benign

0.92

Polyphen

0.0010

Vest4

0.26

MVP

0.52

MPC

0.41

ClinPred

0.012

GERP RS

5.1

Varity_R

0.058

gMVP

0.29

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

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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

Computational scores

Splicing

Publications

Other links and lift over