9-99150189-A-G

Variant names:

• chr9-99150189-A-G
• rs334348
• NM_004612.4:c.*884A>G

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.*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
• Publications: 57 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=-0.8).
• BP6: Variant 9-99150189-A-G is Benign according to our data. Variant chr9-99150189-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	NM_004612.4	MANE Select	c.*884A>G		3_prime_UTR	Exon 9 of 9	NP_004603.1
	TGFBR1	NR_176360.1		n.2500A>G		non_coding_transcript_exon	Exon 9 of 9
	TGFBR1	NR_176361.1		n.2605A>G		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.*884A>G		3_prime_UTR	Exon 9 of 9	ENSP00000364133.4
	TGFBR1	ENST00000552516.5	TSL:1	c.*884A>G		3_prime_UTR	Exon 9 of 9	ENSP00000447297.1
	TGFBR1	ENST00000374990.6	TSL:1	c.*884A>G		3_prime_UTR	Exon 8 of 8	ENSP00000364129.2

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

African (AFR) AF: 0.305 AC: 454 AN: 1490

American (AMR) AF: 0.258 AC: 244 AN: 944

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 563 AN: 2414

East Asian (EAS) AF: 0.546 AC: 3641 AN: 6672

South Asian (SAS) AF: 0.373 AC: 123 AN: 330

European-Finnish (FIN) AF: 0.266 AC: 102 AN: 384

Middle Eastern (MID) AF: 0.212 AC: 45 AN: 212

European-Non Finnish (NFE) AF: 0.262 AC: 5851 AN: 22310

Other (OTH) AF: 0.285 AC: 861 AN: 3026

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

African (AFR) AF: 0.316 AC: 13105 AN: 41484

American (AMR) AF: 0.284 AC: 4344 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 844 AN: 3466

East Asian (EAS) AF: 0.469 AC: 2428 AN: 5176

South Asian (SAS) AF: 0.323 AC: 1562 AN: 4830

European-Finnish (FIN) AF: 0.212 AC: 2247 AN: 10602

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18046 AN: 67972

Other (OTH) AF: 0.281 AC: 594 AN: 2112

Alfa AF: 0.259 Hom.: 8123

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loeys-Dietz syndrome 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loeys-Dietz syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome Benign:1

Nov 15, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.2
DANN	Benign	0.87
PhyloP100		0.60
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: rs334348; hg19: chr9-101912471;