rs149533093

Positions:

• chr1-218405178-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000366930.9(TGFB2):​c.356C>T​(p.Pro119Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000639 in 1,584,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P119S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: TGFB2 ENST00000366930.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 4.80

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07172263).
• BP6: Variant 1-218405178-C-T is Benign according to our data. Variant chr1-218405178-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213840.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=8}. Variant chr1-218405178-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000473 (72/152204) while in subpopulation NFE AF= 0.000794 (54/68020). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.356C>T	p.Pro119Leu	missense_variant	2/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.440C>T	p.Pro147Leu	missense_variant	3/8		NP_001129071.1
TGFB2	NR_138148.2	n.1722C>T		non_coding_transcript_exon_variant	2/7
TGFB2	NR_138149.2	n.1806C>T		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.356C>T	p.Pro119Leu	missense_variant	2/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.440C>T	p.Pro147Leu	missense_variant	3/8	1		ENSP00000355896
TGFB2	ENST00000488793.1	n.20C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000389 AC: 93 AN: 238938 Hom.: 0 AF XY: 0.000426 AC XY: 55 AN XY: 129088

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000251

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.000656

Gnomad OTH exome AF: 0.000527

GnomAD4 exome AF: 0.000656 AC: 940 AN: 1432328 Hom.: 0 Cov.: 30 AF XY: 0.000631 AC XY: 447 AN XY: 707848

Gnomad4 AFR exome AF: 0.000277

Gnomad4 AMR exome AF: 0.0000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000408

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.000781

Gnomad4 OTH exome AF: 0.000560

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74400

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000642 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000371 AC: 45

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 06, 2019	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP4,BP4,BP6. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	TGFB2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2023	Variant summary: TGFB2 c.356C>T (p.Pro119Leu) results in a non-conservative amino acid change located in the TGF-beta, propeptide domain (IPR001111) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 238938 control chromosomes (gnomAD). The observed variant frequency is approximately 311 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. The following publication has been ascertained in the context of this evaluation (PMID: 22772371). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as VUS (n=4) and benign/likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 04, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aortic aneurysm Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Feb 16, 2017

- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

TGFB2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	-0.022
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.13
Sift	Benign	0.32	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;B
Vest4		0.31
MVP		0.30
MPC		0.73
ClinPred		0.030	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.48

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: rs149533093; hg19: chr1-218578520; COSMIC: COSV65110710;