6-82365725-G-T

Position:

• chr6-82365725-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001376922.1(TPBG):​c.764G>T​(p.Arg255Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPBG NM_001376922.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

Genes affected

TPBG (HGNC:12004): (trophoblast glycoprotein) This gene encodes a leucine-rich transmembrane glycoprotein that may be involved in cell adhesion. The encoded protein is an oncofetal antigen that is specific to trophoblast cells. In adults this protein is highly expressed in many tumor cells and is associated with poor clinical outcome in numerous cancers. Alternate splicing in the 5' UTR results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27155346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPBG	NM_001376922.1	c.764G>T	p.Arg255Leu	missense_variant	2/2	ENST00000369750.4	NP_001363851.1
TPBG	NM_001166392.2	c.764G>T	p.Arg255Leu	missense_variant	2/2		NP_001159864.1
TPBG	NM_006670.5	c.764G>T	p.Arg255Leu	missense_variant	3/3		NP_006661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPBG	ENST00000369750.4	c.764G>T	p.Arg255Leu	missense_variant	2/2	1	NM_001376922.1	ENSP00000358765.4
TPBG	ENST00000535040.4	c.764G>T	p.Arg255Leu	missense_variant	3/3	2		ENSP00000441219.1
TPBG	ENST00000543496.3	c.764G>T	p.Arg255Leu	missense_variant	2/2	2		ENSP00000440049.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.764G>T (p.R255L) alteration is located in exon 3 (coding exon 1) of the TPBG gene. This alteration results from a G to T substitution at nucleotide position 764, causing the arginine (R) at amino acid position 255 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.0074
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.51	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.034	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.76	P;P;P
Vest4		0.19
MutPred		0.51		Loss of methylation at R255 (P = 0.0301);Loss of methylation at R255 (P = 0.0301);Loss of methylation at R255 (P = 0.0301);
MVP		0.67
MPC		0.81
ClinPred		0.64	D
GERP RS		4.7
Varity_R		0.58
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-83075442;