rs334358

Variant names:

• chr9-99148331-G-T
• rs334358
• NM_004612.4:c.1386+547G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004612.4(TGFBR1):​c.1386+547G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,142 control chromosomes in the GnomAD database, including 2,372 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2372 hom., cov: 32)
• Consequence: TGFBR1 NM_004612.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.1386+547G>T		intron_variant	Intron 8 of 8	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.1386+547G>T		intron_variant	Intron 8 of 8	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26025 AN: 152024 Hom.: 2361 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.171 AC: 26069 AN: 152142 Hom.: 2372 Cov.: 32 AF XY: 0.164 AC XY: 12226 AN XY: 74364

African (AFR) AF: 0.175 AC: 7243 AN: 41506

American (AMR) AF: 0.135 AC: 2065 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3470

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5190

South Asian (SAS) AF: 0.105 AC: 505 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1384 AN: 10582

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13576 AN: 67982

Other (OTH) AF: 0.171 AC: 362 AN: 2114

Alfa AF: 0.190 Hom.: 376

Bravo AF: 0.169

Asia WGS AF: 0.0700 AC: 247 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.53
PhyloP100		-0.098
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: rs334358; hg19: chr9-101910613;