rs1553303161

Positions:

• chr1-218435964-TTCAA-TG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003238.6(TGFB2):​c.755-5_755-2delTCAAinsG variant causes a splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB2 NM_003238.6 splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.77

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-218435965-TCAA-G is Pathogenic according to our data. Variant chr1-218435965-TCAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528887.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.755-5_755-2delTCAAinsG		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.839-5_839-2delTCAAinsG		splice_acceptor_variant, splice_region_variant, intron_variant			NP_001129071.1
TGFB2	NR_138148.2	n.2121-120_2121-117delTCAAinsG		intron_variant
TGFB2	NR_138149.2	n.2205-120_2205-117delTCAAinsG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.755-5_755-2delTCAAinsG		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.839-5_839-2delTCAAinsG		splice_acceptor_variant, splice_region_variant, intron_variant		1		ENSP00000355896.4
TGFB2	ENST00000479322.1	n.239-5_239-2delTCAAinsG		splice_acceptor_variant, splice_region_variant, intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2017

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TGFB2 are known to be pathogenic (PMID: 22772371, 22772368). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TGFB2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the TGFB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553303161; hg19: chr1-218609307;