9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC

Position:

• chr9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

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

The NM_004612.4(TGFBR1):​c.73_78dupGCGGCG​(p.Ala25_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 0.000159 in 1,043,494 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 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 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]

TGFBR1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-99105255-T-TGGCGGC is Benign according to our data. Variant chr9-99105255-T-TGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496264.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_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.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	1/9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 27 AN: 142424 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000413

Gnomad SAS AF: 0.000434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000232

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000154 AC: 139 AN: 900968 Hom.: 0 Cov.: 7 AF XY: 0.000151 AC XY: 64 AN XY: 422764

Gnomad4 AFR exome AF: 0.000230

Gnomad4 AMR exome AF: 0.000357

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000498

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.000160

GnomAD4 genome AF: 0.000189 AC: 27 AN: 142526 Hom.: 0 Cov.: 30 AF XY: 0.000144 AC XY: 10 AN XY: 69400

Gnomad4 AFR AF: 0.000178

Gnomad4 AMR AF: 0.0000687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000415

Gnomad4 SAS AF: 0.000434

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000232

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2023	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	Jan 13, 2024	This variant, c.73_78dup, results in the insertion of 2 amino acid(s) of the TGFBR1 protein (p.Ala25_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 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. ClinVar contains an entry for this variant (Variation ID: 496264). 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. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2017	Variant summary: The TGFBR1 c.73_78dupGCGGCG (p.Ala25_Ala26dup) variant involves the duplication of six nucleotides in a repetitive region. One in silico tools predicts a deleterious outcome for this variant. The frequency of this variant in population databases is not available due to lack of coverage or very low coverage of the chromosomal region. This variant was reported to be found in 1/2436 control chromosomes in the literature at a frequency of 0.0004105, which is approximately 263 times the estimated maximal expected allele frequency of a pathogenic TGFBR1 variant (0.0000016), suggesting this variant is possibly a benign polymorphism, although the allele number is very low. This variant has been reported in a sporadic BrC patient without evidence of causality. The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2024	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;