9-99105207-T-C

Variant names:

• chr9-99105207-T-C
• NM_004612.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004612.4(TGFBR1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000107 in 930,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.334
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 70 codons. Genomic position: 99128965. Lost 0.138 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 930704 Hom.: 0 Cov.: 30 AF XY: 0.00000229 AC XY: 1 AN XY: 436470

⚠️ 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: 18386

American (AMR) AF: 0.00 AC: 0 AN: 3528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8690

East Asian (EAS) AF: 0.00 AC: 0 AN: 12542

South Asian (SAS) AF: 0.0000548 AC: 1 AN: 18236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2140

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826032

Other (OTH) AF: 0.00 AC: 0 AN: 33504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Nov 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change affects the initiator methionine of the TGFBR1 mRNA. The next in-frame methionine is located at codon 70. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.48	T
PhyloP100		-0.33
PROVEAN	Benign	-0.31	N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0070	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0030	B;B;.
Vest4		0.64
MutPred		0.92		Gain of glycosylation at M1 (P = 0.0089);Gain of glycosylation at M1 (P = 0.0089);Gain of glycosylation at M1 (P = 0.0089);
MVP		0.98
ClinPred		0.21	T
GERP RS		1.5
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.2
Varity_R		0.29
gMVP		0.57
Mutation Taster		=15/185	disease causing

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

hg19: chr9-101867489;