rs1800471

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000660.7(TGFB1):c.74G>C(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0711 in 1,543,868 control chromosomes in the GnomAD database, including 4,202 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.063 ( 356 hom., cov: 32)

Exomes 𝑓: 0.072 ( 3846 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.754

Publications

522 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 links:

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM91 links:

ENSG00000255730 (HGNC:):

ENSG00000255730 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=0.002168864).

BP6

Variant 19-41352971-C-G is Benign according to our data. Variant chr19-41352971-C-G is described in ClinVar as Benign. ClinVar VariationId is 38902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 7	1	NM_000660.7	ENSP00000221930.4

Frequencies

GnomAD3 genomes

AF:

0.0630

AC:

9580

AN:

152132

Hom.:

354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0647

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0750

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0775

Gnomad OTH

AF:

0.0550

GnomAD2 exomes

AF:

0.0565

AC:

8035

AN:

142282

AF XY:

0.0592

show subpopulations

Gnomad AFR exome

AF:

0.0649

Gnomad AMR exome

AF:

0.0341

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.000818

Gnomad FIN exome

AF:

0.0347

Gnomad NFE exome

AF:

0.0732

Gnomad OTH exome

AF:

0.0571

GnomAD4 exome

AF:

0.0719

AC:

100121

AN:

1391618

Hom.:

3846

Cov.:

AF XY:

0.0717

AC XY:

49252

AN XY:

687184

show subpopulations

African (AFR)

AF:

0.0623

AC:

1972

AN:

31654

American (AMR)

AF:

0.0369

AC:

1324

AN:

35926

Ashkenazi Jewish (ASJ)

AF:

0.0412

AC:

1038

AN:

25166

East Asian (EAS)

AF:

0.000390

AC:

AN:

35914

South Asian (SAS)

AF:

0.0759

AC:

6049

AN:

79676

European-Finnish (FIN)

AF:

0.0394

AC:

1542

AN:

39170

Middle Eastern (MID)

AF:

0.0667

AC:

379

AN:

5686

European-Non Finnish (NFE)

AF:

0.0777

AC:

83964

AN:

1080410

Other (OTH)

AF:

0.0662

AC:

3839

AN:

58016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

5779

11558

17336

23115

28894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3140

6280

9420

12560

15700

<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:

0.0630

AC:

9586

AN:

152250

Hom.:

356

Cov.:

AF XY:

0.0607

AC XY:

4518

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0645

AC:

2680

AN:

41556

American (AMR)

AF:

0.0407

AC:

623

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

151

AN:

3472

East Asian (EAS)

AF:

0.00136

AC:

AN:

5156

South Asian (SAS)

AF:

0.0761

AC:

367

AN:

4824

European-Finnish (FIN)

AF:

0.0310

AC:

329

AN:

10620

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0775

AC:

5269

AN:

68004

Other (OTH)

AF:

0.0544

AC:

115

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

471

942

1412

1883

2354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0554

Hom.:

Bravo

AF:

0.0629

TwinsUK

AF:

0.0798

AC:

296

ALSPAC

AF:

0.0838

AC:

323

ESP6500AA

AF:

0.0454

AC:

187

ESP6500EA

AF:

0.0491

AC:

396

ExAC

AF:

0.0264

AC:

2615

Asia WGS

AF:

0.0300

AC:

104

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.97

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

PhyloP100

0.75

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.50

REVEL

Benign

0.067

Sift

Benign

0.25

Sift4G

Benign

0.28

Vest4

0.16

ClinPred

0.018

GERP RS

2.8

PromoterAI

-0.0081

Neutral

(source)

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over