9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGC

Position:

• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000374994.9(TGFBR1):​c.73_78del​(p.Ala25_Ala26del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,043,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000070 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TGFBR1 ENST00000374994.9 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 9-99105255-TGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 263873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.73_78del	p.Ala25_Ala26del	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.73_78del	p.Ala25_Ala26del	inframe_deletion	1/9	1	NM_004612.4	ENSP00000364133	P4

Frequencies

GnomAD3 genomes AF: 0.0000702 AC: 10 AN: 142424 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000413

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00347

Gnomad NFE AF: 0.0000619

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000400 AC: 36 AN: 900942 Hom.: 0 AF XY: 0.0000402 AC XY: 17 AN XY: 422746

Gnomad4 AFR exome AF: 0.000345

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000137

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.000194

Gnomad4 NFE exome AF: 0.0000272

Gnomad4 OTH exome AF: 0.0000958

GnomAD4 genome AF: 0.0000702 AC: 10 AN: 142524 Hom.: 0 Cov.: 30 AF XY: 0.000101 AC XY: 7 AN XY: 69398

Gnomad4 AFR AF: 0.0000254

Gnomad4 AMR AF: 0.0000687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000415

Gnomad4 SAS AF: 0.000217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000619

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 19, 2015	This alteration is classified as 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. -

TGFBR1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2021

- -

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;