9-99105255-TGGCGGCGGC-T

Position:

• chr9-99105255-TGGCGGCGGC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004612.4(TGFBR1):​c.70_78del​(p.Ala24_Ala26del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0928 in 1,043,304 control chromosomes in the GnomAD database, including 4,897 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (585 hom., cov: 30)
  • Exomes 𝑓: 0.095 (4312 hom.)
• Consequence: TGFBR1 NM_004612.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• 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 -16 ACMG points.

• BP6: Variant 9-99105255-TGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99105255-TGGCGGCGGC-T is described in Lovd as [Likely_pathogenic]. Variant chr9-99105255-TGGCGGCGGC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.70_78del	p.Ala24_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.70_78del	p.Ala24_Ala26del	inframe_deletion	1/9	1	NM_004612.4	ENSP00000364133	P4

Frequencies

GnomAD3 genomes AF: 0.0815 AC: 11610 AN: 142372 Hom.: 586 Cov.: 30

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0629

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.00165

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.0909

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0903

GnomAD3 exomes AF: 0.0582 AC: 34 AN: 584 Hom.: 1 AF XY: 0.0765 AC XY: 26 AN XY: 340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0837

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0946 AC: 85196 AN: 900830 Hom.: 4312 AF XY: 0.0941 AC XY: 39758 AN XY: 422658

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.0378

Gnomad4 ASJ exome AF: 0.0589

Gnomad4 EAS exome AF: 0.000434

Gnomad4 SAS exome AF: 0.0375

Gnomad4 FIN exome AF: 0.0807

Gnomad4 NFE exome AF: 0.0991

Gnomad4 OTH exome AF: 0.0790

GnomAD4 genome AF: 0.0815 AC: 11615 AN: 142474 Hom.: 585 Cov.: 30 AF XY: 0.0812 AC XY: 5633 AN XY: 69374

Gnomad4 AFR AF: 0.0589

Gnomad4 AMR AF: 0.0628

Gnomad4 ASJ AF: 0.0784

Gnomad4 EAS AF: 0.00166

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0893

Bravo AF: 0.0738

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jun 05, 2017	BA1, BS1, BP3, BP6; This alteration has an allele frequency that is greater than 5% healthy populations (ExAC/gnomAD), has an allele frequency that is greater than expected for the associated disease, is an in-frame deletion/insertion in a repetitive region without a known function, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2013	This alteration is classified as benign based on a combination of the following: 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. -

Loeys-Dietz syndrome 1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 19, 2015	- -

Loeys-Dietz syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 09, 2022

- -

Thoracic aortic aneurysm Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

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;