9-99105255-T-TGGCGGC

Variant names:

• chr9-99105255-T-TGGCGGC
• rs11466445
• NM_004612.4:c.73_78dupGCGGCG

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.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
• 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-T-TGGCGGC is Benign according to our data. Variant chr9-99105255-T-TGGCGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496264.
• BS2: High AC in GnomAd4 at 27 AD 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.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	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.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.73_78dupGCGGCG	p.Ala25_Ala26dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000364129.2	P36897-3

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

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

African (AFR) AF: 0.000230 AC: 4 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: 0.00 AC: 0 AN: 9216

South Asian (SAS) AF: 0.000498 AC: 9 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: 0.000149 AC: 120 AN: 807768

Other (OTH) AF: 0.000160 AC: 5 AN: 31332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000178 AC: 7 AN: 39330

American (AMR) AF: 0.0000687 AC: 1 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: 0.000434 AC: 2 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: 0.000232 AC: 15 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
-	2	1	Familial thoracic aortic aneurysm and aortic dissection (3)
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99
Mutation Taster		=73/27	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;