6-82365458-A-G

Variant names:

• chr6-82365458-A-G
• rs142127308
• NM_001376922.1:c.497A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001376922.1(TPBG):​c.497A>G​(p.Asn166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000695 in 1,610,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: TPBG NM_001376922.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.080173165).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPBG	NM_001376922.1	c.497A>G	p.Asn166Ser	missense_variant	Exon 2 of 2	ENST00000369750.4	NP_001363851.1
TPBG	NM_001166392.2	c.497A>G	p.Asn166Ser	missense_variant	Exon 2 of 2		NP_001159864.1
TPBG	NM_006670.5	c.497A>G	p.Asn166Ser	missense_variant	Exon 3 of 3		NP_006661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPBG	ENST00000369750.4	c.497A>G	p.Asn166Ser	missense_variant	Exon 2 of 2	1	NM_001376922.1	ENSP00000358765.4
TPBG	ENST00000535040.4	c.497A>G	p.Asn166Ser	missense_variant	Exon 3 of 3	2		ENSP00000441219.1
TPBG	ENST00000543496.3	c.497A>G	p.Asn166Ser	missense_variant	Exon 2 of 2	2		ENSP00000440049.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000729 AC: 18 AN: 247016 Hom.: 0 AF XY: 0.0000748 AC XY: 10 AN XY: 133774

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000713 AC: 104 AN: 1458406 Hom.: 0 Cov.: 30 AF XY: 0.0000703 AC XY: 51 AN XY: 725470

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000699

Gnomad4 FIN exome AF: 0.0000951

Gnomad4 NFE exome AF: 0.0000720

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74338

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497A>G (p.N166S) alteration is located in exon 3 (coding exon 1) of the TPBG gene. This alteration results from a A to G substitution at nucleotide position 497, causing the asparagine (N) at amino acid position 166 to be replaced by a serine (S). 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	0.082
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.59	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.36	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.084	B;B;B
Vest4		0.22
MVP		0.33
MPC		0.78
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142127308; hg19: chr6-83075175;