chr19-41348306-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000660.7(TGFB1):c.505G>C(p.Glu169Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96

Publications

6 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
inflammatory bowel disease, immunodeficiency, and encephalopathy
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Uncertain_significance. The variant received 4 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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7 link	c.505G>C	p.Glu169Gln	missense_variant	Exon 2 of 7	ENST00000221930.6	NP_000651.3	P01137A0A499FJK2
TGFB1	XM_011527242.3 link	c.505G>C	p.Glu169Gln	missense_variant	Exon 2 of 7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFB1	ENST00000221930.6 link	c.505G>C	p.Glu169Gln	missense_variant	Exon 2 of 7	1	NM_000660.7	ENSP00000221930.4	A0A499FJK2
TGFB1	ENST00000597453.1 link	n.36G>C		non_coding_transcript_exon_variant	Exon 1 of 3	1
TGFB1	ENST00000600196.2 link	c.505G>C	p.Glu169Gln	missense_variant	Exon 2 of 6	5		ENSP00000504008.1	A0A7I2YQL8
TGFB1	ENST00000677934.1 link	c.505G>C	p.Glu169Gln	missense_variant	Exon 2 of 5			ENSP00000504769.1	A0A7I2V5Z9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251336

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460814

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726726

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111674

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 169 of the TGFB1 protein (p.Glu169Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TGFB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1920186). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TGFB1 protein function with a negative predictive value of 80%. This variant disrupts the p.Glu169 amino acid residue in TGFB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17433803, 29230158, 29620655). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

-0.16

PhyloP100

5.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.58

MutPred

0.63

Gain of MoRF binding (P = 0.0233);

MVP

0.76

MPC

1.7

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=45/55

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over