9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGC

Variant names:

• chr9-99105255-TGGCGGCGGCGGC-T
• rs11466445
• NM_004612.4:c.67_78delGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_004612.4(TGFBR1):​c.67_78delGCGGCGGCGGCG​(p.Ala23_Ala26del) variant causes a conservative 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.84
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004612.4
• 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 VariationId is 516727.
• BS2: High AC in GnomAd4 at 14 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004612.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	NM_004612.4	MANE Select	c.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 8	NP_001394345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.67_78delGCGGCGGCGGCG	p.Ala23_Ala26del	conservative_inframe_deletion	Exon 1 of 8	ENSP00000364129.2	P36897-3

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

African (AFR) AF: 0.000115 AC: 2 AN: 17388

American (AMR) AF: 0.000357 AC: 1 AN: 2804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7300

East Asian (EAS) AF: 0.000109 AC: 1 AN: 9216

South Asian (SAS) AF: 0.0000554 AC: 1 AN: 18064

European-Finnish (FIN) AF: 0.000194 AC: 1 AN: 5142

Middle Eastern (MID) AF: 0.000512 AC: 1 AN: 1952

European-Non Finnish (NFE) AF: 0.0000730 AC: 59 AN: 807708

Other (OTH) AF: 0.0000319 AC: 1 AN: 31332

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

African (AFR) AF: 0.0000509 AC: 2 AN: 39330

American (AMR) AF: 0.000206 AC: 3 AN: 14554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3342

East Asian (EAS) AF: 0.000415 AC: 2 AN: 4824

South Asian (SAS) AF: 0.00 AC: 0 AN: 4608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000108 AC: 7 AN: 64622

Other (OTH) AF: 0.00 AC: 0 AN: 1984

Alfa AF: 0.00 Hom.: 37

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	not provided (1)
-	1	-	TGFBR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=191/9	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11466445; hg19: chr9-101867537;