chr9-99137916-T-TTGG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate

The NM_004612.4(TGFBR1):​c.633_635dup​(p.Gly212_Lys212insGly) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TGFBR1
NM_004612.4 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.0960
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 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_004612.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004612.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 9-99137916-T-TTGG is Pathogenic according to our data. Variant chr9-99137916-T-TTGG is described in ClinVar as [Pathogenic]. Clinvar id is 520221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGFBR1NM_004612.4 linkuse as main transcriptc.633_635dup p.Gly212_Lys212insGly inframe_insertion 4/9 ENST00000374994.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFBR1ENST00000374994.9 linkuse as main transcriptc.633_635dup p.Gly212_Lys212insGly inframe_insertion 4/91 NM_004612.4 P4P36897-1

Frequencies

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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 21, 2016The c.633_635dupTGG pathogenic mutation (also known as p.G212dup), located in coding exon 4 of the TGFBR1 gene, results from an in-frame duplication of TGG at nucleotide positions 633 to 635. This results in the duplication of an extra residue between codons 212 and 213. This alteration was confirmed as de novo in a proband tested by our laboratory whose clinical features are consistent with Loeys-Dietz syndrome. Based on the available evidence, c.633_635dupTGG is classified as a pathogenic mutation. -

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: rs1554700603; hg19: chr9-101900198; API