1-91698089-G-T

Variant names:

• chr1-91698089-G-T
• rs2228363
• NM_003243.5:c.2329C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 17/24 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
• Publications: 15 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003243.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR3	NM_003243.5	MANE Select	c.2329C>A	p.Pro777Thr	missense splice_region	Exon 15 of 17	NP_003234.2	Q03167-1
	TGFBR3	NM_001195683.2		c.2326C>A	p.Pro776Thr	missense splice_region	Exon 15 of 17	NP_001182612.1	A0A0A8KWK3
	TGFBR3	NM_001195684.1		c.2326C>A	p.Pro776Thr	missense splice_region	Exon 16 of 18	NP_001182613.1	A0A0A8KWK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR3	ENST00000212355.9	TSL:1 MANE Select	c.2329C>A	p.Pro777Thr	missense splice_region	Exon 15 of 17	ENSP00000212355.4	Q03167-1
	TGFBR3	ENST00000525962.5	TSL:1	c.2329C>A	p.Pro777Thr	missense splice_region	Exon 14 of 16	ENSP00000436127.1	Q03167-1
	TGFBR3	ENST00000370399.6	TSL:1	c.2326C>A	p.Pro776Thr	missense splice_region	Exon 16 of 18	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 26

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.18
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		4.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.040
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.0050	B
Vest4		0.35
MutPred		0.34		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
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs2228363; hg19: chr1-92163646;