Variant 9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004612.4(TGFBR1):c.76_78dupGCG(p.Ala26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,043,488 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

TGFBR1
NM_004612.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.987

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]

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 9-99105255-T-TGGC is Benign according to our data. Variant chr9-99105255-T-TGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213864.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=8}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000856 (122/142522) while in subpopulation SAS AF= 0.0026 (12/4608). AF 95% confidence interval is 0.0015. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4 link	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	ENST00000374994.9	NP_004603.1	P36897-1Q5T7S2B4DXN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 link	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

AF:

0.000857

AC:

122

AN:

142420

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000689

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00227

Gnomad SAS

AF:

0.00260

Gnomad FIN

AF:

0.000614

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000928

Gnomad OTH

AF:

0.00153

GnomAD3 exomes

AF:

0.00171

AC:

AN:

584

Hom.:

AF XY:

0.00

AC XY:

AN XY:

340

show subpopulations

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:

0.00246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00139

AC:

1255

AN:

900966

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

596

AN XY:

422760

show subpopulations

Gnomad4 AFR exome

AF:

0.00115

Gnomad4 AMR exome

AF:

0.000713

Gnomad4 ASJ exome

AF:

0.000137

Gnomad4 EAS exome

AF:

0.00109

Gnomad4 SAS exome

AF:

0.00205

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00140

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.000856

AC:

122

AN:

142522

Hom.:

Cov.:

AF XY:

0.000879

AC XY:

AN XY:

69398

show subpopulations

Gnomad4 AFR

AF:

0.000687

Gnomad4 AMR

AF:

0.000275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00228

Gnomad4 SAS

AF:

0.00260

Gnomad4 FIN

AF:

0.000614

Gnomad4 NFE

AF:

0.000928

Gnomad4 OTH

AF:

0.00151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Apr 17, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGFBR1 c.76_78dupGCG (p.Ala26dup) results in an in-frame duplication that is predicted to duplicate one amino acid into the encoded protein. The variant allele was found at a frequency of 0.0013 in 1045682 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 702 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06). The variant, c.76_78dupGCG, has been reported in the literature in an individual with suspected Loeys-Dietz Syndrome (example, Seo_2018), but was also found in healthy controls (Samowitz_2001, Rego_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect for this variant on either targeting to or translocation across the endoplasmic reticulum membrane as well as no impact on TGF-beta signaling (example, Pasche_1999, Pasche_2005). The following publications have been ascertained in the context of this evaluation (PMID: 21461994, 10582683, 16204663, 30487145, 11746979, 29768367, 19401691, 17575241, 15505640, 17613544). ClinVar contains an entry for this variant (Variation ID: 213864). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 02, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29768367, 30487145, 11746979, 10582683, 16204663) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR1: BS1 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TGFBR1-related disorder

Benign:1

Mar 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Multiple self-healing squamous epithelioma

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

South Asian population allele frequency is 0.1502% (rs11466445, 12/4610 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over