rs334349

Variant names:

• chr9-99152105-G-A
• rs334349
• NM_004612.4:c.*2800G>A

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.*2800G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 206,368 control chromosomes in the GnomAD database, including 9,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6167 hom., cov: 31)
  • Exomes 𝑓: 0.31 (2902 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.02
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-99152105-G-A is Benign according to our data. Variant chr9-99152105-G-A is described in ClinVar as Benign. ClinVar VariationId is 364155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 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.*2800G>A		3_prime_UTR	Exon 9 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.*2800G>A		3_prime_UTR	Exon 9 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.*2800G>A		3_prime_UTR	Exon 8 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.*2800G>A		3_prime_UTR	Exon 9 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552516.5	TSL:1	c.*2800G>A		3_prime_UTR	Exon 9 of 9	ENSP00000447297.1	P36897-2
	TGFBR1	ENST00000374990.6	TSL:1	c.*2800G>A		3_prime_UTR	Exon 8 of 8	ENSP00000364129.2	P36897-3

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42447 AN: 151784 Hom.: 6148 Cov.: 31

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.306 AC: 16682 AN: 54466 Hom.: 2902 Cov.: 0 AF XY: 0.304 AC XY: 7708 AN XY: 25324

African (AFR) AF: 0.280 AC: 695 AN: 2484

American (AMR) AF: 0.277 AC: 425 AN: 1532

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 802 AN: 3486

East Asian (EAS) AF: 0.539 AC: 4586 AN: 8508

South Asian (SAS) AF: 0.363 AC: 170 AN: 468

European-Finnish (FIN) AF: 0.206 AC: 7 AN: 34

Middle Eastern (MID) AF: 0.224 AC: 78 AN: 348

European-Non Finnish (NFE) AF: 0.262 AC: 8669 AN: 33112

Other (OTH) AF: 0.278 AC: 1250 AN: 4494

GnomAD4 genome AF: 0.280 AC: 42517 AN: 151902 Hom.: 6167 Cov.: 31 AF XY: 0.278 AC XY: 20642 AN XY: 74232

African (AFR) AF: 0.298 AC: 12320 AN: 41394

American (AMR) AF: 0.282 AC: 4304 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3468

East Asian (EAS) AF: 0.468 AC: 2412 AN: 5150

South Asian (SAS) AF: 0.321 AC: 1545 AN: 4812

European-Finnish (FIN) AF: 0.212 AC: 2237 AN: 10566

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18020 AN: 67958

Other (OTH) AF: 0.279 AC: 588 AN: 2106

Alfa AF: 0.270 Hom.: 6999

Bravo AF: 0.283

Asia WGS AF: 0.398 AC: 1383 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.032
DANN	Benign	0.79
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs334349; hg19: chr9-101914387;