9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGC

Position:

• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGC

Variant summary

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

The ENST00000374994.9(TGFBR1):​c.67_78del​(p.Ala23_Ala26del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000776 in 1,043,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: TGFBR1 ENST00000374994.9 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-99105255-TGGCGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGCGGC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 516727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.67_78del	p.Ala23_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.67_78del	p.Ala23_Ala26del	inframe_deletion	1/9	1	NM_004612.4	ENSP00000364133	P4

Frequencies

GnomAD3 genomes AF: 0.0000983 AC: 14 AN: 142424 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000413

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000108

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000744 AC: 67 AN: 900906 Hom.: 0 AF XY: 0.0000781 AC XY: 33 AN XY: 422736

Gnomad4 AFR exome AF: 0.000115

Gnomad4 AMR exome AF: 0.000357

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.000194

Gnomad4 NFE exome AF: 0.0000730

Gnomad4 OTH exome AF: 0.0000319

GnomAD4 genome AF: 0.0000982 AC: 14 AN: 142526 Hom.: 0 Cov.: 30 AF XY: 0.0000865 AC XY: 6 AN XY: 69400

Gnomad4 AFR AF: 0.0000509

Gnomad4 AMR AF: 0.000206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000415

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000108

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This variant, c.67_78del, results in the deletion of 4 amino acid(s) of the TGFBR1 protein (p.Ala23_Ala26del), 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: 516727). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2021	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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2022

The TGFBR1 c.67_78del12 variant is predicted to result in an in-frame deletion (p.Ala23_Ala26del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.29% of alleles (or four heterozygous alleles) in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101867537-TGGCGGCGGCGGC-T). The allele frequency data for this variant should be interpreted with caution due to insufficient coverage. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2022

See Variant Classification Assertion Criteria. -

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;