rs11568778

Variant names:

• chr9-99138128-A-G
• rs11568778
• NM_004612.4:c.805+39A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-99138128-A-G
• chr9-99138128-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004612.4(TGFBR1):​c.805+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,549,336 control chromosomes in the GnomAD database, including 5,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (591 hom., cov: 32)
  • Exomes 𝑓: 0.026 (4463 hom.)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.83
• Publications: 7 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 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
• multiple self-healing squamous epithelioma

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-99138128-A-G is Benign according to our data. Variant chr9-99138128-A-G is described in ClinVar as Benign. ClinVar VariationId is 259453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 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.805+39A>G		intron	N/A	NP_004603.1
	TGFBR1	NM_001306210.2		c.817+39A>G		intron	N/A	NP_001293139.1
	TGFBR1	NM_001407416.1		c.817+39A>G		intron	N/A	NP_001394345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.805+39A>G		intron	N/A	ENSP00000364133.4
	TGFBR1	ENST00000552516.5	TSL:1	c.817+39A>G		intron	N/A	ENSP00000447297.1
	TGFBR1	ENST00000374990.6	TSL:1	c.574+39A>G		intron	N/A	ENSP00000364129.2

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4869 AN: 152174 Hom.: 594 Cov.: 32

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0665 AC: 16409 AN: 246870 AF XY: 0.0635

Gnomad AFR exome AF: 0.00570

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0256 AC: 35779 AN: 1397042 Hom.: 4463 Cov.: 22 AF XY: 0.0273 AC XY: 19054 AN XY: 698608

African (AFR) AF: 0.00524 AC: 168 AN: 32086

American (AMR) AF: 0.129 AC: 5732 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 49 AN: 25688

East Asian (EAS) AF: 0.409 AC: 16062 AN: 39270

South Asian (SAS) AF: 0.104 AC: 8773 AN: 84738

European-Finnish (FIN) AF: 0.0102 AC: 540 AN: 52930

Middle Eastern (MID) AF: 0.0135 AC: 76 AN: 5650

European-Non Finnish (NFE) AF: 0.00219 AC: 2305 AN: 1054000

Other (OTH) AF: 0.0356 AC: 2074 AN: 58180

GnomAD4 genome AF: 0.0320 AC: 4869 AN: 152294 Hom.: 591 Cov.: 32 AF XY: 0.0371 AC XY: 2762 AN XY: 74458

African (AFR) AF: 0.00563 AC: 234 AN: 41580

American (AMR) AF: 0.100 AC: 1530 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.407 AC: 2105 AN: 5170

South Asian (SAS) AF: 0.118 AC: 568 AN: 4824

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68020

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0168 Hom.: 160

Bravo AF: 0.0375

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Multiple self-healing squamous epithelioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.9
DANN	Benign	0.73
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11568778; hg19: chr9-101900410; COSMIC: COSV66627100; COSMIC: COSV66627100;