1-91695778-TGG-GCT

Variant names:

• chr1-91695778-TGC-GCT
• NM_003243.5:c.2330-1_2331delGCAinsAGC
• TGFBR3 p.Pro777Arg

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_003243.5(TGFBR3):​c.2330-1_2331delGCAinsAGC​(p.Pro777Arg) variant causes a splice acceptor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 33)
• Consequence: TGFBR3 NM_003243.5 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.55
• Publications: 0 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 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04225352 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 1, new splice context is: cggtttctctcctttataAGcat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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.2330-1_2331delGCAinsAGC	p.Pro777Arg	splice_acceptor missense splice_region intron	N/A	NP_003234.2	Q03167-1
	TGFBR3	NM_001195683.2		c.2327-1_2328delGCAinsAGC	p.Pro776Arg	splice_acceptor missense splice_region intron	N/A	NP_001182612.1	A0A0A8KWK3
	TGFBR3	NM_001195684.1		c.2327-1_2328delGCAinsAGC	p.Pro776Arg	splice_acceptor missense splice_region intron	N/A	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.2330-1_2331delGCAinsAGC	p.Pro777Arg	splice_acceptor missense splice_region intron	N/A	ENSP00000212355.4	Q03167-1
	TGFBR3	ENST00000525962.5	TSL:1	c.2330-1_2331delGCAinsAGC	p.Pro777Arg	splice_acceptor missense splice_region intron	N/A	ENSP00000436127.1	Q03167-1
	TGFBR3	ENST00000370399.6	TSL:1	c.2327-1_2328delGCAinsAGC	p.Pro776Arg	splice_acceptor missense splice_region intron	N/A	ENSP00000359426.2	Q03167-2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-92161335;