rs200482214

chr19-41348345-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) 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	UniProt
TGFB1	NM_000660.7	c.466C>T	p.Arg156Cys	missense_variant	2/7	ENST00000221930.6
TGFB1	XM_011527242.3	c.466C>T	p.Arg156Cys	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB1	ENST00000221930.6	c.466C>T	p.Arg156Cys	missense_variant	2/7	1	NM_000660.7	P1
TGFB1	ENST00000600196.2	c.466C>T	p.Arg156Cys	missense_variant	2/6	5
TGFB1	ENST00000677934.1	c.466C>T	p.Arg156Cys	missense_variant	2/5
TGFB1	ENST00000597453.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151992 Hom.: 0 Cov.: 30

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: 17 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727018

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: 5 AN: 151992 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74238

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.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.84
MutPred		0.80		Loss of MoRF binding (P = 9e-04);
MVP		0.92
MPC		2.0
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs200482214; hg19: chr19-41854250; COSMIC: COSV99700133; COSMIC: COSV99700133;