rs538831129

Positions:

• chr9-99105255-T-TGGCGGCGGC
• chr9-99105255-T-TGGCGGC
• chr9-99105255-T-TGGCGGCGGCGGCGGC
• chr9-99105255-T-TGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGC-T
• chr9-99105255-T-TGGCGGCGGCGGCGGCGGC
• chr9-99105255-TGGC-T
• chr9-99105255-TGGCGGCGGCGGCGGC-T
• chr9-99105255-TGGCGGCGGCGGC-T
• chr9-99105255-T-TGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-T
• chr9-99105255-TGGCGGC-T

Variant summary

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

The NM_004612.4(TGFBR1):​c.70_78dup​(p.Ala24_Ala26dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,043,394 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 0.000063 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-99105255-T-TGGCGGCGGC is Benign according to our data. Variant chr9-99105255-T-TGGCGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408570.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.70_78dup	p.Ala24_Ala26dup	inframe_insertion	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_78dup	p.Ala24_Ala26dup	inframe_insertion	1/9	1	NM_004612.4	ENSP00000364133	P4

Frequencies

GnomAD3 genomes AF: 0.0000632 AC: 9 AN: 142424 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000774

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000610 AC: 55 AN: 900970 Hom.: 0 Cov.: 7 AF XY: 0.0000615 AC XY: 26 AN XY: 422764

Gnomad4 AFR exome AF: 0.0000575

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000644

Gnomad4 OTH exome AF: 0.0000319

GnomAD4 genome AF: 0.0000632 AC: 9 AN: 142424 Hom.: 0 Cov.: 30 AF XY: 0.0000577 AC XY: 4 AN XY: 69286

Gnomad4 AFR AF: 0.0000510

Gnomad4 AMR AF: 0.0000688

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000774

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 10, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 22, 2022	This variant, c.70_78dup, results in the insertion of 3 amino acid(s) of the TGFBR1 protein (p.Ala24_Ala26dup), 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 poor data quality 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: 408570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2020	The TGFBR1 c.70_78dup; p.Ala24_Ala26dup variant (rs11466445), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 408570). This variant is found in the general population with an overall allele frequency of 0.008% (2/23,942 alleles) in the Genome Aggregation Database. This variant is three amino acid, in-frame expansion of the polyalanine track in exon 1 of TGFBR1. In-frame contractions of this track are found at relatively high frequency in the general population and are mostly considered benign (ClinVar; Skoglund 2007). Expansions of this track are less frequent, although a single alanine duplication has been reported in a patient with a Marfan-related disorder (Seo 2018). Based on the available information, the clinical significance of the p.Ala24_Ala26dup variant is uncertain. Seo GH et al. The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. Medicine (Baltimore). 2018 May;97(20):e10767. Skoglund J et al. Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. Clin Cancer Res. 2007 Jun 15;13(12):3748-52. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	- -

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;