rs1800470

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000221930.6(TGFB1):c.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,527,994 control chromosomes in the GnomAD database, including 280,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 26724 hom., cov: 33)

Exomes 𝑓: 0.61 ( 253856 hom. )

Consequence

TGFB1
ENST00000221930.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:2

Conservation

PhyloP100: 0.760

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.7511124E-6).

BP6

Variant 19-41353016-G-A is Benign according to our data. Variant chr19-41353016-G-A is described in ClinVar as [Benign]. Clinvar id is 12534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41353016-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7 link	c.29C>T	p.Pro10Leu	missense_variant	1/7	ENST00000221930.6	NP_000651.3	P01137A0A499FJK2
TGFB1	XM_011527242.3 link	c.29C>T	p.Pro10Leu	missense_variant	1/7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6 link	c.29C>T	p.Pro10Leu	missense_variant	1/7	1	NM_000660.7	ENSP00000221930.4		A0A499FJK2

Frequencies

GnomAD3 genomes

AF:

0.589

AC:

89408

AN:

151872

Hom.:

26723

Cov.:

show subpopulations

Gnomad AFR

AF:

0.575

Gnomad AMI

AF:

0.785

Gnomad AMR

AF:

0.518

Gnomad ASJ

AF:

0.501

Gnomad EAS

AF:

0.443

Gnomad SAS

AF:

0.544

Gnomad FIN

AF:

0.714

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.611

Gnomad OTH

AF:

0.563

GnomAD3 exomes

AF:

0.552

AC:

71740

AN:

129938

Hom.:

19769

AF XY:

0.554

AC XY:

39248

AN XY:

70790

show subpopulations

Gnomad AFR exome

AF:

0.567

Gnomad AMR exome

AF:

0.477

Gnomad ASJ exome

AF:

0.494

Gnomad EAS exome

AF:

0.449

Gnomad SAS exome

AF:

0.537

Gnomad FIN exome

AF:

0.707

Gnomad NFE exome

AF:

0.604

Gnomad OTH exome

AF:

0.559

GnomAD4 exome

AF:

0.606

AC:

834062

AN:

1376004

Hom.:

253856

Cov.:

AF XY:

0.603

AC XY:

409363

AN XY:

678490

show subpopulations

Gnomad4 AFR exome

AF:

0.565

Gnomad4 AMR exome

AF:

0.482

Gnomad4 ASJ exome

AF:

0.491

Gnomad4 EAS exome

AF:

0.479

Gnomad4 SAS exome

AF:

0.538

Gnomad4 FIN exome

AF:

0.712

Gnomad4 NFE exome

AF:

0.622

Gnomad4 OTH exome

AF:

0.581

GnomAD4 genome

AF:

0.588

AC:

89439

AN:

151990

Hom.:

26724

Cov.:

AF XY:

0.589

AC XY:

43749

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.574

Gnomad4 AMR

AF:

0.517

Gnomad4 ASJ

AF:

0.501

Gnomad4 EAS

AF:

0.444

Gnomad4 SAS

AF:

0.544

Gnomad4 FIN

AF:

0.714

Gnomad4 NFE

AF:

0.611

Gnomad4 OTH

AF:

0.559

Alfa

AF:

0.504

Hom.:

2560

Bravo

AF:

0.573

TwinsUK

AF:

0.629

AC:

2334

ALSPAC

AF:

0.622

AC:

2398

ExAC

AF:

0.488

AC:

27708

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inflammatory bowel disease, immunodeficiency, and encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Meckel syndrome, type 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Diaphyseal dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Cystic fibrosis

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 15, 2008

- -

Breast cancer, invasive, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0000058

MetaSVM

Benign

-0.95

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.34

REVEL

Benign

0.017

Sift

Benign

0.83

Sift4G

Benign

0.18

Vest4

0.098

MPC

0.67

ClinPred

0.0082

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over