rs11466445

Positions:

• chr9-99105255-TGGCGGCGGCGGCGGCGGC-T
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC
• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004612.4(TGFBR1):​c.61_78del​(p.Ala21_Ala26del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,043,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.61_78del	p.Ala21_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.61_78del	p.Ala21_Ala26del	inframe_deletion	1/9	1	NM_004612.4	ENSP00000364133	P4

Frequencies

GnomAD3 genomes AF: 0.00000702 AC: 1 AN: 142424 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 13 AN: 900968 Hom.: 0 AF XY: 0.0000213 AC XY: 9 AN XY: 422762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000248

Gnomad4 OTH exome AF: 0.0000319

GnomAD4 genome AF: 0.00000702 AC: 1 AN: 142424 Hom.: 0 Cov.: 30 AF XY: 0.0000144 AC XY: 1 AN XY: 69286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This variant, c.61_78del, results in the deletion of 6 amino acid(s) of the TGFBR1 protein (p.Ala21_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 insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. 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. -

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;