9-99105255-TGGCGGCGGCGGCGGCGGC-TGGC

Position:

• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004612.4(TGFBR1):​c.64_78delGCGGCGGCGGCGGCG​(p.Ala22_Ala26del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,043,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.84

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]

TGFBR1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-99105255-TGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496263.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	1/9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	1/9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.0000211 AC: 3 AN: 142422 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 21 AN: 900966 Hom.: 0 AF XY: 0.0000331 AC XY: 14 AN XY: 422760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000223

Gnomad4 OTH exome AF: 0.0000319

GnomAD4 genome AF: 0.0000211 AC: 3 AN: 142422 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 69286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000464

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The TGFBR1 c.64_78delGCGGCGGCGGCGGCG (p.Ala22_Ala26del) variant involves the deletion of 15 nucleotides and results an inframe deletion of 5 out of 9 consecutive Alanines in N-terminus of TGFBR1 protein. These repeating Alanines are not located in any known domain (InterPro). One in silico tool predicts a benign outcome for this variant. There is no or extremely low coverage in this region in control databases (ExAC, gnomAD, ESP, or 1000Gs). c.70_78delGCGGCGGCG (rs11466445), a shorter deletion in this Alanine repeat region, is classified as benign/likely benign by 8 clinical diagnostics laboratories in ClinVar. However, the variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 14, 2022	This variant, c.64_78del, results in the deletion of 5 amino acid(s) of the TGFBR1 protein (p.Ala22_Ala26del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496263). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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: rs11466445; hg19: chr9-101867537;