rs1590

Variant names:

• chr9-99153883-T-G
• rs1590
• NM_004612.4:c.*4578T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-99153883-T-G
• chr9-99153883-T-C

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.*4578T>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 0.29 in 212,666 control chromosomes in the GnomAD database, including 9,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6341 hom., cov: 32)
  • Exomes 𝑓: 0.31 (3232 hom.)
• Consequence: TGFBR1 NM_004612.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0830
• Publications: 42 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=-0.99).
• BP6: Variant 9-99153883-T-G is Benign according to our data. Variant chr9-99153883-T-G is described in ClinVar as Benign. ClinVar VariationId is 364189.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	NM_004612.4	MANE Select	c.*4578T>G		3_prime_UTR	Exon 9 of 9	NP_004603.1	P36897-1
	TGFBR1	NM_001306210.2		c.*4578T>G		3_prime_UTR	Exon 9 of 9	NP_001293139.1	P36897-2
	TGFBR1	NM_001407416.1		c.*4578T>G		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.*4578T>G		3_prime_UTR	Exon 9 of 9	ENSP00000364133.4	P36897-1
	TGFBR1	ENST00000552573.7	TSL:4	c.*4578T>G		3_prime_UTR	Exon 9 of 9	ENSP00000447182.3	F8W0K6
	TGFBR1	ENST00000546584.2	TSL:4	c.*4578T>G		3_prime_UTR	Exon 9 of 9	ENSP00000447707.3	B4DY26

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43004 AN: 151954 Hom.: 6322 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.309 AC: 18695 AN: 60594 Hom.: 3232 Cov.: 0 AF XY: 0.306 AC XY: 8626 AN XY: 28156

African (AFR) AF: 0.291 AC: 796 AN: 2736

American (AMR) AF: 0.285 AC: 498 AN: 1746

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 926 AN: 3834

East Asian (EAS) AF: 0.542 AC: 5006 AN: 9244

South Asian (SAS) AF: 0.355 AC: 191 AN: 538

European-Finnish (FIN) AF: 0.300 AC: 15 AN: 50

Middle Eastern (MID) AF: 0.227 AC: 88 AN: 388

European-Non Finnish (NFE) AF: 0.264 AC: 9782 AN: 37024

Other (OTH) AF: 0.277 AC: 1393 AN: 5034

GnomAD4 genome AF: 0.283 AC: 43074 AN: 152072 Hom.: 6341 Cov.: 32 AF XY: 0.281 AC XY: 20929 AN XY: 74354

African (AFR) AF: 0.308 AC: 12779 AN: 41468

American (AMR) AF: 0.283 AC: 4328 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3470

East Asian (EAS) AF: 0.470 AC: 2426 AN: 5166

South Asian (SAS) AF: 0.324 AC: 1559 AN: 4816

European-Finnish (FIN) AF: 0.211 AC: 2235 AN: 10582

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

European-Non Finnish (NFE) AF: 0.266 AC: 18063 AN: 67964

Other (OTH) AF: 0.281 AC: 593 AN: 2110

Alfa AF: 0.252 Hom.: 4174

Bravo AF: 0.287

Asia WGS AF: 0.399 AC: 1387 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	-0.99
CADD	Benign	1.1
DANN	Benign	0.46
PhyloP100		-0.083
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: rs1590; hg19: chr9-101916165;