9-99128944-G-T

Position:

• chr9-99128944-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004612.4(TGFBR1):​c.187G>T​(p.Asp63Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D63N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TGFBR1. . Gene score misZ 2.7935 (greater than the threshold 3.09). Trascript score misZ 3.6468 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, multiple self-healing squamous epithelioma, Loeys-Dietz syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR1	NM_004612.4	c.187G>T	p.Asp63Tyr	missense_variant	2/9	ENST00000374994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR1	ENST00000374994.9	c.187G>T	p.Asp63Tyr	missense_variant	2/9	1	NM_004612.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.46	P;B;.
Vest4		0.61
MutPred		0.68		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.91
MPC		1.1
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-101891226;