chr9-99105255-TGGCGGCGGC-T

Variant names:

• chr9-99105255-TGGCGGCGGC-T
• rs11466445
• NM_004612.4:c.70_78delGCGGCGGCG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_004612.4(TGFBR1):​c.70_78delGCGGCGGCG​(p.Ala24_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 0.0928 in 1,043,304 control chromosomes in the GnomAD database, including 4,897 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (585 hom., cov: 30)
  • Exomes 𝑓: 0.095 (4312 hom.)
• Consequence: TGFBR1 NM_004612.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004612.4
• BP6: Variant 9-99105255-TGGCGGCGGC-T is Benign according to our data. Variant chr9-99105255-TGGCGGCGGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

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.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.70_78delGCGGCGGCG	p.Ala24_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.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.70_78delGCGGCGGCG	p.Ala24_Ala26del	conservative_inframe_deletion	Exon 1 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.0815 AC: 11610 AN: 142372 Hom.: 586 Cov.: 30

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0629

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.00165

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.0909

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0903

GnomAD2 exomes AF: 0.0582 AC: 34 AN: 584 AF XY: 0.0765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0837

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0946 AC: 85196 AN: 900830 Hom.: 4312 AF XY: 0.0941 AC XY: 39758 AN XY: 422658

African (AFR) AF: 0.0552 AC: 959 AN: 17388

American (AMR) AF: 0.0378 AC: 106 AN: 2804

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 430 AN: 7300

East Asian (EAS) AF: 0.000434 AC: 4 AN: 9216

South Asian (SAS) AF: 0.0375 AC: 678 AN: 18062

European-Finnish (FIN) AF: 0.0807 AC: 415 AN: 5140

Middle Eastern (MID) AF: 0.0605 AC: 118 AN: 1952

European-Non Finnish (NFE) AF: 0.0991 AC: 80010 AN: 807642

Other (OTH) AF: 0.0790 AC: 2476 AN: 31326

GnomAD4 genome AF: 0.0815 AC: 11615 AN: 142474 Hom.: 585 Cov.: 30 AF XY: 0.0812 AC XY: 5633 AN XY: 69374

African (AFR) AF: 0.0589 AC: 2314 AN: 39314

American (AMR) AF: 0.0628 AC: 914 AN: 14550

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 262 AN: 3342

East Asian (EAS) AF: 0.00166 AC: 8 AN: 4824

South Asian (SAS) AF: 0.0363 AC: 167 AN: 4604

European-Finnish (FIN) AF: 0.137 AC: 1117 AN: 8136

Middle Eastern (MID) AF: 0.0909 AC: 24 AN: 264

European-Non Finnish (NFE) AF: 0.102 AC: 6562 AN: 64606

Other (OTH) AF: 0.0893 AC: 177 AN: 1982

Alfa AF: 0.0343 Hom.: 37

Bravo AF: 0.0738

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	2	Loeys-Dietz syndrome (2)
-	1	1	Loeys-Dietz syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Thoracic aortic aneurysm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=197/3	polymorphism (auto)

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; COSMIC: COSV66624995;