chr1-218347023-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS2

The NM_003238.6(TGFB2):c.322A>T(p.Met108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,447,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TGFB2
NM_003238.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.97

Publications

1 publications found

Variant links:

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) 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 TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 links:

TGFB2-AS1 (HGNC:50628): (TGFB2 antisense RNA 1 (head to head))

TGFB2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6 link	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 7	ENST00000366930.9	NP_003229.1	P61812-1Q59EG9
TGFB2	NM_001135599.4 link	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 8		NP_001129071.1	P61812-2Q59EG9
TGFB2	NR_138148.2 link	n.1688A>T		non_coding_transcript_exon_variant	Exon 1 of 7
TGFB2	NR_138149.2 link	n.1688A>T		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9 link	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 7	1	NM_003238.6	ENSP00000355897.4		P61812-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1447626

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33180

American (AMR)

AF:

0.00

AC:

AN:

42332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.00

AC:

AN:

39154

South Asian (SAS)

AF:

0.00

AC:

AN:

84694

European-Finnish (FIN)

AF:

0.0000767

AC:

AN:

52130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104736

Other (OTH)

AF:

0.00

AC:

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 4

Uncertain:1

Oct 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFB2-related disease. This sequence change replaces methionine with leucine at codon 108 of the TGFB2 protein (p.Met108Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Uncertain

0.082

MutationAssessor

Pathogenic

3.1

M;M

PhyloP100

6.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.033

D;T

Polyphen

0.84

P;P

Vest4

0.44

MutPred

0.71

Loss of ubiquitination at K105 (P = 0.0613);Loss of ubiquitination at K105 (P = 0.0613);

MVP

0.89

MPC

0.74

ClinPred

0.96

GERP RS

5.5

Varity_R

0.61

gMVP

0.66

Mutation Taster

=76/24

polymorphism

(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

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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