9-99132728-G-T

Variant names:

• chr9-99132728-G-T
• rs1554699638
• NM_004612.4:c.563G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_004612.4(TGFBR1):​c.563G>T​(p.Gly188Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 10.0
• Publications: 2 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_004612.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-99132728-G-T is Pathogenic according to our data. Variant chr9-99132728-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520227.

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.563G>T	p.Gly188Val	missense	Exon 3 of 9	NP_004603.1
	TGFBR1	NM_001306210.2		c.575G>T	p.Gly192Val	missense	Exon 3 of 9	NP_001293139.1
	TGFBR1	NM_001407416.1		c.575G>T	p.Gly192Val	missense	Exon 3 of 8	NP_001394345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR1	ENST00000374994.9	TSL:1 MANE Select	c.563G>T	p.Gly188Val	missense	Exon 3 of 9	ENSP00000364133.4
	TGFBR1	ENST00000552516.5	TSL:1	c.575G>T	p.Gly192Val	missense	Exon 3 of 9	ENSP00000447297.1
	TGFBR1	ENST00000374990.6	TSL:1	c.343+3628G>T		intron	N/A	ENSP00000364129.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727220

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Sep 25, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G188V variant (also known as c.563G>T), located in coding exon 3 of the TGFBR1 gene, results from a G to T substitution at nucleotide position 563. The glycine at codon 188 is replaced by valine, an amino acid with dissimilar properties. This alteration alters the first amino acid of the highly conserved GS domain signature sequence (GSGSGLP) found in type I TGF beta receptors. This variant has been observed in at least three individuals with a personal and/or family history that is consistent with TGFBR1-related Loeys-Dietz syndrome and segregated with disease in at least one family (Ambry internal data; Ziganshin BA et al. Ann. Thorac. Surg. 2015;100:1604-11; Yamada S. Front Physiol. 2021 Aug;12:715687). Cells from aortic tissue of a heterozygous mouse model with this variant showed distorted and ruptured elastic fibers; however, the clinical relevance of this finding is unclear (Yamada S. Front Physiol. 2021 Aug;12:715687). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is likely pathogenic for TGFBR1-related Loeys-Dietz syndrome.

not provided Uncertain:1

Sep 12, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies show that this variant is embryonic lethality in homozygous state, and results in disorganized aortic elastic fibers and reduced lifespan in the heterozygous state, and causes disregulation of TGF-b signaling (Yamada et al., 2021).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26188975, 34456753, 29543232)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.88		Loss of disorder (P = 0.0434)
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.99
gMVP		0.89
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554699638; hg19: chr9-101895010;