1-91698089-G-T

Position:

• chr1-91698089-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003243.5(TGFBR3):​c.2329C>A​(p.Pro777Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P777S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR3 NM_003243.5 missense, splice_region
• Scores: Splicing: ADA: 0.003517
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.47

Genes affected

TGFBR3 (HGNC:11774): (transforming growth factor beta receptor 3) This locus encodes the transforming growth factor (TGF)-beta type III receptor. The encoded receptor is a membrane proteoglycan that often functions as a co-receptor with other TGF-beta receptor superfamily members. Ectodomain shedding produces soluble TGFBR3, which may inhibit TGFB signaling. Decreased expression of this receptor has been observed in various cancers. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR3	NM_003243.5	c.2329C>A	p.Pro777Thr	missense_variant, splice_region_variant	15/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9	c.2329C>A	p.Pro777Thr	missense_variant, splice_region_variant	15/17	1	NM_003243.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T;.;.;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;.;N;.
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.40	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0050	B;B;B;B
Vest4		0.35
MutPred		0.34		Gain of glycosylation at P777 (P = 0.0146);.;Gain of glycosylation at P777 (P = 0.0146);.;
MVP		0.54
MPC		0.25
ClinPred		0.57	D
GERP RS		5.0
Varity_R		0.12
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.024
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

Publications

LitVar

Other links and lift over

dbSNP: rs2228363; hg19: chr1-92163646;