rs398122883

Variant names:

• chr1-218346994-ACTACGCCAAGGAGGT-A
• rs398122883
• NM_003238.6:c.294_308delCTACGCCAAGGAGGT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_003238.6(TGFB2):​c.294_308delCTACGCCAAGGAGGT​(p.Tyr99_Val103del) variant causes a disruptive inframe deletion 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFB2 NM_003238.6 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.97

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003238.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-218346994-ACTACGCCAAGGAGGT-A is Pathogenic according to our data. Variant chr1-218346994-ACTACGCCAAGGAGGT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37086.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr1-218346994-ACTACGCCAAGGAGGT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.294_308delCTACGCCAAGGAGGT	p.Tyr99_Val103del	disruptive_inframe_deletion	Exon 1 of 7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.294_308delCTACGCCAAGGAGGT	p.Tyr99_Val103del	disruptive_inframe_deletion	Exon 1 of 8		NP_001129071.1
TGFB2	NR_138148.2	n.1660_1674delCTACGCCAAGGAGGT		non_coding_transcript_exon_variant	Exon 1 of 7
TGFB2	NR_138149.2	n.1660_1674delCTACGCCAAGGAGGT		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.294_308delCTACGCCAAGGAGGT	p.Tyr99_Val103del	disruptive_inframe_deletion	Exon 1 of 7	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.294_308delCTACGCCAAGGAGGT	p.Tyr99_Val103del	disruptive_inframe_deletion	Exon 1 of 8	1		ENSP00000355896.4
TGFB2	ENST00000488793.1	n.-43_-29delCTACGCCAAGGAGGT		upstream_gene_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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Loeys-Dietz syndrome 4 Pathogenic:2 Uncertain:1

Oct 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has been observed in individual(s) with TGFB2-related conditions (PMID: 22772368, Invitae). ClinVar contains an entry for this variant (Variation ID: 37086). This variant is not present in population databases (ExAC no frequency). This variant, c.294_308del, results in the deletion of 5 amino acid(s) of the TGFB2 protein (p.Ala100_Tyr104del), but otherwise preserves the integrity of the reading frame. -

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Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Jul 08, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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: rs398122883; hg19: chr1-218520336;