chr9-99105255-TGGCGGCGGCGGCGGC-T

Variant names:

• chr9-99105255-TGGCGGCGGCGGCGGC-T
• rs11466445
• NM_004612.4:c.64_78delGCGGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_004612.4(TGFBR1):​c.64_78delGCGGCGGCGGCGGCG​(p.Ala22_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 0.000023 in 1,043,388 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• 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 -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004612.4
• BP6: Variant 9-99105255-TGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGCGGCGGC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496263.

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.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.64_78delGCGGCGGCGGCGGCG	p.Ala22_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.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.64_78delGCGGCGGCGGCGGCG	p.Ala22_Ala26del	conservative_inframe_deletion	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.0000211 AC: 3 AN: 142422 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 21 AN: 900966 Hom.: 0 AF XY: 0.0000331 AC XY: 14 AN XY: 422760

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17388

American (AMR) AF: 0.00 AC: 0 AN: 2804

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 9216

South Asian (SAS) AF: 0.000111 AC: 2 AN: 18064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1952

European-Non Finnish (NFE) AF: 0.0000223 AC: 18 AN: 807766

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000212210), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000211 AC: 3 AN: 142422 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 69286

African (AFR) AF: 0.00 AC: 0 AN: 39216

American (AMR) AF: 0.00 AC: 0 AN: 14538

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.00 AC: 0 AN: 4610

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000464 AC: 3 AN: 64630

Other (OTH) AF: 0.00 AC: 0 AN: 1962

Alfa AF: 0.00 Hom.: 37

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Familial thoracic aortic aneurysm and aortic dissection (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=157/43	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;