rs1800472

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000660.7(TGFB1):c.788C>T(p.Thr263Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0237 in 1,614,180 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T263T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 82 hom., cov: 32)

Exomes 𝑓: 0.024 ( 648 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.37

Publications

104 publications found

Variant links:

Genes affected

TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TGFB1 Gene-Disease associations (from GenCC):

Camurati-Engelmann disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics, PanelApp Australia
inflammatory bowel disease, immunodeficiency, and encephalopathy
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TGFB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000660.7

BP4

Computational evidence support a benign effect (MetaRNN=0.0014927983).

BP6

Variant 19-41341955-G-A is Benign according to our data. Variant chr19-41341955-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000660.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	NM_000660.7	MANE Select	c.788C>T	p.Thr263Ile	missense	Exon 5 of 7	NP_000651.3	P01137

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGFB1	ENST00000221930.6	TSL:1 MANE Select	c.788C>T	p.Thr263Ile	missense	Exon 5 of 7	ENSP00000221930.4	A0A499FJK2
TGFB1	ENST00000890114.1		c.791C>T	p.Thr264Ile	missense	Exon 5 of 7	ENSP00000560173.1
TGFB1	ENST00000966383.1		c.728C>T	p.Thr243Ile	missense	Exon 5 of 7	ENSP00000636442.1

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3458

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0315

GnomAD2 exomes

AF:

0.0259

AC:

6506

AN:

251068

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0188

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0384

Gnomad NFE exome

AF:

0.0293

Gnomad OTH exome

AF:

0.0331

GnomAD4 exome

AF:

0.0238

AC:

34837

AN:

1461856

Hom.:

648

Cov.:

AF XY:

0.0240

AC XY:

17459

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00430

AC:

144

AN:

33476

American (AMR)

AF:

0.0185

AC:

827

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3120

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0107

AC:

922

AN:

86258

European-Finnish (FIN)

AF:

0.0352

AC:

1882

AN:

53410

Middle Eastern (MID)

AF:

0.0579

AC:

334

AN:

5768

European-Non Finnish (NFE)

AF:

0.0232

AC:

25788

AN:

1111994

Other (OTH)

AF:

0.0301

AC:

1819

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

2139

4278

6416

8555

10694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.0227

AC:

3454

AN:

152324

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1757

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00447

AC:

186

AN:

41592

American (AMR)

AF:

0.0262

AC:

400

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

395

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00891

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0440

AC:

467

AN:

10610

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1866

AN:

68040

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

178

355

533

710

888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0276

Hom.:

391

Bravo

AF:

0.0206

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0245

AC:

2975

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0330

EpiControl

AF:

0.0367

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.058

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.87

PhyloP100

5.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.1

REVEL

Benign

0.10

Sift

Benign

0.40

Sift4G

Benign

0.44

Vest4

0.052

MPC

1.0

ClinPred

0.011

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=93/7

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

Computational scores

Splicing

Publications

Other links and lift over