1-218434154-G-T

Variant names:

• chr1-218434154-G-T
• rs863223790
• NM_003238.6:c.583G>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003238.6(TGFB2):​c.583G>T​(p.Glu195*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TGFB2 NM_003238.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.70

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-218434154-G-T is Pathogenic according to our data. Variant chr1-218434154-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 213841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-218434154-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.583G>T	p.Glu195*	stop_gained	Exon 3 of 7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.667G>T	p.Glu223*	stop_gained	Exon 4 of 8		NP_001129071.1
TGFB2	NR_138148.2	n.1949G>T		non_coding_transcript_exon_variant	Exon 3 of 7
TGFB2	NR_138149.2	n.2033G>T		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.583G>T	p.Glu195*	stop_gained	Exon 3 of 7	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.667G>T	p.Glu223*	stop_gained	Exon 4 of 8	1		ENSP00000355896.4
TGFB2	ENST00000479322.1	n.29G>T		non_coding_transcript_exon_variant	Exon 1 of 5	3
TGFB2	ENST00000488793.1	n.247G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:1

Mar 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu195*) in the TGFB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGFB2 are known to be pathogenic (PMID: 22772368, 22772371, 30739908). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TGFB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213841). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Sep 03, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu195Ter (GAA>TAA): c.583 G>T in exon 3 of the TGFB2 gene (NM_003238.3). Mutations in TGFB2 are found in approximately 1% of individuals with Loeys-Dietz syndrome (LDS; Loeys BL and Dietz HC, 2013). Patients with a mutation in TGFB2 may present with a milder phenotype, although features of classic LDS may occur (Boileau et al., 2012). Features common in carriers of mutations in TGFB2 include club feet and mitral valve disease (Loeys BL and Dietz HC, 2013).The E195X mutation in the TGFB2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. E195X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the TGFB2 gene have been reported in association with a TAAD-related disorder. In summary, E195X in the TGFB2 gene is interpreted as a disease-causing mutation. This variant was found in TAAD. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.95
GERP RS		5.9

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: rs863223790; hg19: chr1-218607496;