rs200482214

Positions:

chr19-41348345-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000660.7(TGFB1):c.466C>T(p.Arg156Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000660.7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 19-41348345-G-A is Pathogenic according to our data. Variant chr19-41348345-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1498982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41348345-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7 linkuse as main transcript	c.466C>T	p.Arg156Cys	missense_variant	2/7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3 linkuse as main transcript	c.466C>T	p.Arg156Cys	missense_variant	2/7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TGFB1	ENST00000221930.6 linkuse as main transcript	c.466C>T	p.Arg156Cys	missense_variant	2/7	1	NM_000660.7	ENSP00000221930	P1
TGFB1	ENST00000600196.2 linkuse as main transcript	c.466C>T	p.Arg156Cys	missense_variant	2/6	5		ENSP00000504008
TGFB1	ENST00000677934.1 linkuse as main transcript	c.466C>T	p.Arg156Cys	missense_variant	2/5			ENSP00000504769
TGFB1	ENST00000597453.1 linkuse as main transcript			upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461444

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000804

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the TGFB1 protein (p.Arg156Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant TGFB1-related conditions (PMID: 11260231, 15894597, 23453470, 23824952, 31899347). ClinVar contains an entry for this variant (Variation ID: 1498982). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFB1 protein function. Experimental studies have shown that this missense change affects TGFB1 function (PMID: 19584867). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 18, 2021	- -

TGFB1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

The TGFB1 c.466C>T variant is predicted to result in the amino acid substitution p.Arg156Cys. This variant has been reported in multiple unrelated individuals with Camurati-Engelmann disease (Hecht et al. 2001. PubMed ID: 11260231; Janssens et al. 2005. PubMed ID: 15894597; Collet et al. 2013. PubMed ID: 23824952; Savoie et al. 2013. PubMed ID: 23453470). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1498982/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.19

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.84

MutPred

0.80

Loss of MoRF binding (P = 9e-04);

MVP

0.92

MPC

2.0

ClinPred

1.0

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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