rs587776866

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_004612.4(TGFBR1):​c.806-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TGFBR1
NM_004612.4 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11044974 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 36, new splice context is: tcagctctggttggtgtcAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGFBR1NM_004612.4 linkuse as main transcriptc.806-2A>C splice_acceptor_variant, intron_variant ENST00000374994.9 NP_004603.1 P36897-1Q5T7S2B4DXN7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGFBR1ENST00000374994.9 linkuse as main transcriptc.806-2A>C splice_acceptor_variant, intron_variant 1 NM_004612.4 ENSP00000364133.4 P36897-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Loeys-Dietz syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 13, 2024This variant causes an A>C nucleotide substitution at the -2 position of intron 4 of the TGFBR1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An ex vivo minigene splicing assay has shown that this variant causes a deletion of 76 nucleotides from exon 5, predicted to result in frameshift and premature truncation (PMID: 29706644). This variant has been reported in two individuals from one family affected with multiple self-healing squamous epithelioma (PMID: 21358634, 23358096). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TGFBR1 truncation and splice variants variants in autosomal dominant Loeys-Dietz syndrome or thoracic aortic aneurysm and dissection is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Multiple self-healing squamous epithelioma Other:1
risk factor, no assertion criteria providedliterature onlyOMIMFeb 27, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
29
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.93
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.93
Position offset: 2

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: rs587776866; hg19: chr9-101904816; API