rs398122883

Positions:

• chr1-218346994-ACTACGCCAAGGAGGT-A

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_308del​(p.Ala100_Tyr104del) variant causes a 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 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/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.294_308del	p.Ala100_Tyr104del	inframe_deletion	1/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.294_308del	p.Ala100_Tyr104del	inframe_deletion	1/8		NP_001129071.1
TGFB2	NR_138148.2	n.1660_1674del		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2	n.1660_1674del		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.294_308del	p.Ala100_Tyr104del	inframe_deletion	1/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.294_308del	p.Ala100_Tyr104del	inframe_deletion	1/8	1		ENSP00000355896
TGFB2	ENST00000488793.1			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

Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 08, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2020	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. 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). -

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;