rs869312904

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003238.6(TGFB2):​c.1022_1026del​(p.Tyr341CysfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Consequence

TGFB2
NM_003238.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 1-218437430-GTACAA-G is Pathogenic according to our data. Variant chr1-218437430-GTACAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 224873.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-218437430-GTACAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGFB2NM_003238.6 linkuse as main transcriptc.1022_1026del p.Tyr341CysfsTer26 frameshift_variant 6/7 ENST00000366930.9
TGFB2NM_001135599.4 linkuse as main transcriptc.1106_1110del p.Tyr369CysfsTer26 frameshift_variant 7/8
TGFB2NR_138148.2 linkuse as main transcriptn.2273_2277del non_coding_transcript_exon_variant 6/7
TGFB2NR_138149.2 linkuse as main transcriptn.2357_2361del non_coding_transcript_exon_variant 7/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFB2ENST00000366930.9 linkuse as main transcriptc.1022_1026del p.Tyr341CysfsTer26 frameshift_variant 6/71 NM_003238.6 P1P61812-1
TGFB2ENST00000366929.4 linkuse as main transcriptc.1106_1110del p.Tyr369CysfsTer26 frameshift_variant 7/81 P61812-2
TGFB2ENST00000479322.1 linkuse as main transcriptn.506_510del non_coding_transcript_exon_variant 4/53

Frequencies

GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:2
Pathogenic, criteria provided, single submitterresearchBaylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 08, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs398122884; hg19: chr1-218610772; API