9-99105255-T-TGGC

Variant names:

• chr9-99105255-T-TGGC
• rs11466445
• NM_004612.4:c.76_78dupGCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.987

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 -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	c.76_78dupGCG	p.Ala26dup	conservative_inframe_insertion	Exon 1 of 9	ENST00000374994.9	NP_004603.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000857 AC: 122 AN: 142420 Hom.: 0 Cov.: 30

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: 1 AN: 584 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00139 AC: 1255 AN: 900966 Hom.: 2 Cov.: 7 AF XY: 0.00141 AC XY: 596 AN XY: 422760

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.: 0 Cov.: 30 AF XY: 0.000879 AC XY: 61 AN XY: 69398

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:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 10, 2025	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 06, 2023	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TGFBR1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	This variant is associated with the following publications: (PMID: 29768367, 30487145, 11746979, 10582683, 16204663) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 08, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 15, 2019	- -

TGFBR1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

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

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;