chr19-41352745-C-A

Position:

chr19-41352745-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_000660.7(TGFB1):c.300G>T(p.Glu100Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,374 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000060 ( 1 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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

BP4

Computational evidence support a benign effect (MetaRNN=0.022560269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB1	NM_000660.7 linkuse as main transcript	c.300G>T	p.Glu100Asp	missense_variant	1/7	ENST00000221930.6
TGFB1	XM_011527242.3 linkuse as main transcript	c.300G>T	p.Glu100Asp	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TGFB1	ENST00000221930.6 linkuse as main transcript	c.300G>T	p.Glu100Asp	missense_variant	1/7	1	NM_000660.7	P1
TMEM91	ENST00000539627.5 linkuse as main transcript	c.-30+1543C>A		intron_variant		1
TGFB1	ENST00000600196.2 linkuse as main transcript	c.300G>T	p.Glu100Asp	missense_variant	1/6	5
TGFB1	ENST00000677934.1 linkuse as main transcript	c.300G>T	p.Glu100Asp	missense_variant	1/5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000190

AC:

AN:

247566

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134494

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00163

Gnomad NFE exome

AF:

0.0000452

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461202

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726902

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00147

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000631

Hom.:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 100 of the TGFB1 protein (p.Glu100Asp). This variant is present in population databases (rs137864931, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TGFB1-related conditions. 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 not expected to disrupt TGFB1 protein function with a negative predictive value of 80%. 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

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.91

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.73

M_CAP

Benign

0.027

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

REVEL

Benign

0.084

Sift

Benign

0.38

Sift4G

Benign

0.20

Vest4

0.22

MutPred

0.56

Loss of glycosylation at P99 (P = 0.0958);

MVP

0.58

MPC

0.60

ClinPred

0.023

GERP RS

1.8

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