rs1800472

Positions:

chr19-41341955-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000660.7(TGFB1):c.788C>T(p.Thr263Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0237 in 1,614,180 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.023 ( 82 hom., cov: 32)

Exomes 𝑓: 0.024 ( 648 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.37

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 Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0014927983).

BP6

Variant 19-41341955-G-A is Benign according to our data. Variant chr19-41341955-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 38903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41341955-G-A is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7 linkuse as main transcript	c.788C>T	p.Thr263Ile	missense_variant	5/7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3 linkuse as main transcript	c.791C>T	p.Thr264Ile	missense_variant	5/7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TGFB1	ENST00000221930.6 linkuse as main transcript	c.788C>T	p.Thr263Ile	missense_variant	5/7	1	NM_000660.7	ENSP00000221930	P1
TGFB1	ENST00000600196.2 linkuse as main transcript	c.712+215C>T		intron_variant		5		ENSP00000504008
TGFB1	ENST00000677934.1 linkuse as main transcript	c.634+2792C>T		intron_variant				ENSP00000504769
TGFB1	ENST00000598758.5 linkuse as main transcript	n.76C>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3458

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0315

GnomAD3 exomes

AF:

0.0259

AC:

6506

AN:

251068

Hom.:

145

AF XY:

0.0261

AC XY:

3551

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0188

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0384

Gnomad NFE exome

AF:

0.0293

Gnomad OTH exome

AF:

0.0331

GnomAD4 exome

AF:

0.0238

AC:

34837

AN:

1461856

Hom.:

648

Cov.:

AF XY:

0.0240

AC XY:

17459

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00430

Gnomad4 AMR exome

AF:

0.0185

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0107

Gnomad4 FIN exome

AF:

0.0352

Gnomad4 NFE exome

AF:

0.0232

Gnomad4 OTH exome

AF:

0.0301

GnomAD4 genome

AF:

0.0227

AC:

3454

AN:

152324

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1757

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00447

Gnomad4 AMR

AF:

0.0262

Gnomad4 ASJ

AF:

0.114

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00891

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0307

Hom.:

240

Bravo

AF:

0.0206

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0245

AC:

2975

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0330

EpiControl

AF:

0.0367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 26597739, 29728750, 15212689, 17588962, 21777208) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.94

Eigen

Benign

-0.058

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.87

MutationTaster

Benign

0.82

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.1

REVEL

Benign

0.10

Sift

Benign

0.40

Sift4G

Benign

0.44

Vest4

0.052

MPC

1.0

ClinPred

0.011

GERP RS

5.0

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