chr1-218346900-G-A

Position:

• chr1-218346900-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_003238.6(TGFB2):​c.199G>A​(p.Val67Met) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 4.36

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29611892).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000158 (24/152242) while in subpopulation NFE AF= 0.000309 (21/68044). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.199G>A	p.Val67Met	missense_variant	1/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.199G>A	p.Val67Met	missense_variant	1/8
TGFB2	NR_138148.2	n.1565G>A		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2	n.1565G>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.199G>A	p.Val67Met	missense_variant	1/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.199G>A	p.Val67Met	missense_variant	1/8	1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251318 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135884

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1461880 Hom.: 1 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 NFE exome AF: 0.000357

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74370

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 10, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 67 of the TGFB2 protein (p.Val67Met). This variant is present in population databases (rs201761868, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TGFB2-related conditions (PMID: 28139901, 29543232). ClinVar contains an entry for this variant (Variation ID: 213839). 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 TGFB2 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	The TGFB2 c.199G>A; p.Val67Met variant (rs201761868) is reported in the literature in individuals affected with multiple aneurysms and/or pseudoaneurysm syndrome or thoracic aortic aneurysm/aortic dissection (D'Souza 2017, Weerakkody 2018). This variant is reported in ClinVar (Variation ID: 213839), and is found in the non-Finnish European population with an allele frequency of 0.023% (30/129,078 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.272). Due to limited information, the clinical significance of this variant is uncertain at this time. References: D'Souza RS et al. Clinical and genetic characterization of adult patients presenting with non-syndromic vascular aneurysms and dissections. Int Angiol. 2017 Oct;36(5):417-427. PMID: 28139901. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 06, 2020	The p.V67M variant (also known as c.199G>A), located in coding exon 1 of the TGFB2 gene, results from a G to A substitution at nucleotide position 199. The valine at codon 67 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a Thoracic Aortic Aneurysm and Dissection (TAAD) cohort (Weerakkody R et al. Genet. Med., 2018 11;20:1414-1422). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in TGFB2 is predicted to replace valine with methionine at codon 67, p.(Val67Met). The valine residue is highly conserved (100 vertebrates, UCSC), and is located in TGFb propeptide. There is a small physicochemical difference between valine and methionine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (30/129,078 alleles) in the European (non-Finnish) population. This variant has been reported in at least two probands/families with aortic aneurysms (PMID: 28139901, 29543232). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2024	Identified in an individual with aneurysm of the descending thoracoabdominal aorta and in an individual with multiple-aneurysms and/or pseudoaneurysm syndromes (MaPS) (PMID: 29543232, 28139901); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22772371, 28139901, 29543232) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 23, 2023

Variant summary: TGFB2 c.199G>A (p.Val67Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251318 control chromosomes (gnomAD). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Thoracic Aortic Aneurysms And Dissections phenotype (2.5e-05), strongly suggesting that the variant is benign. c.199G>A has been reported in the literature in individuals affected with Thoracic Aortic Aneurysms And Dissections (Boileau_2012, Weerakkody_2018) or multiple-aneurysms and/or pseudoaneurysm syndromes (DSouza_2017). These reports do not provide unequivocal conclusions about association of the variant with Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29543232, 22772371, 28139901). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;D
Vest4		0.35
MVP		0.66
MPC		1.7
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.62

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: rs201761868; hg19: chr1-218520242;