9-99105213-C-T

Variant names:

• chr9-99105213-C-T
• rs1564120661
• NM_004612.4:c.8C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004612.4(TGFBR1):​c.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.222
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17769498).
• BP6: Variant 9-99105213-C-T is Benign according to our data. Variant chr9-99105213-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 623489.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.8C>T	p.Ala3Val	missense_variant	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.8C>T	p.Ala3Val	missense_variant	Exon 1 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000107 AC: 1 AN: 931894 Hom.: 0 Cov.: 30 AF XY: 0.00000229 AC XY: 1 AN XY: 437496

⚠️ 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: 18358

American (AMR) AF: 0.00 AC: 0 AN: 3548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8668

East Asian (EAS) AF: 0.00 AC: 0 AN: 12522

South Asian (SAS) AF: 0.00 AC: 0 AN: 18252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2158

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 827044

Other (OTH) AF: 0.00 AC: 0 AN: 33548

⚠️ 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: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Benign:1

Mar 14, 2019

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8C>T (p.Ala3Val) variant in TGFBR1 is very rare (not reported in population databases) but has a benign computational verdict. Furthermore, the patient who carried this variant had a clinical diagnosis of Marfan syndrome, which was confirmed by MLPA analysis, that identified an intragenic deletion of FBN1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		0.22
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.30	T;D;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.33	B;B;.
Vest4		0.17
MutPred		0.35		Gain of sheet (P = 0.0011);Gain of sheet (P = 0.0011);Gain of sheet (P = 0.0011);
MVP		0.56
MPC		0.51
ClinPred		0.17	T
GERP RS		-0.44
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Varity_R		0.041
gMVP		0.50
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1564120661; hg19: chr9-101867495;