rs334348

Positions:

• chr9-99150189-A-G
• chr9-99150189-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004612.4(TGFBR1):​c.*884A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 189,906 control chromosomes in the GnomAD database, including 8,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6428 hom., cov: 32)
  • Exomes 𝑓: 0.31 (2145 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.601

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-99150189-A-G is Benign according to our data. Variant chr9-99150189-A-G is described in ClinVar as [Benign]. Clinvar id is 364112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.*884A>G		3_prime_UTR_variant	9/9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.*884A>G		3_prime_UTR_variant	9/9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43342 AN: 152004 Hom.: 6408 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.315 AC: 11884 AN: 37782 Hom.: 2145 Cov.: 0 AF XY: 0.315 AC XY: 5518 AN XY: 17542

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.546

Gnomad4 SAS exome AF: 0.373

Gnomad4 FIN exome AF: 0.266

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.285 AC: 43415 AN: 152124 Hom.: 6428 Cov.: 32 AF XY: 0.283 AC XY: 21086 AN XY: 74384

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.323

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.281

Alfa AF: 0.257 Hom.: 6773

Bravo AF: 0.289

Asia WGS AF: 0.398 AC: 1381 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Loeys-Dietz syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 15, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.2
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs334348; hg19: chr9-101912471;