11-75241095-G-T

Variant names:

• chr11-75241095-G-T
• rs540961364
• NM_001195528.2:c.46G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001195528.2(TPBGL):​c.46G>T​(p.Val16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,357,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: TPBGL NM_001195528.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.133

Genes affected

TPBGL (HGNC:44159): (trophoblast glycoprotein like) Predicted to be involved in negative regulation of canonical Wnt signaling pathway. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TPBGL-AS1 (HGNC:55506): (TPBGL antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032713562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPBGL	NM_001195528.2	c.46G>T	p.Val16Leu	missense_variant	Exon 1 of 1	ENST00000562197.3	NP_001182457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPBGL	ENST00000562197.3	c.46G>T	p.Val16Leu	missense_variant	Exon 1 of 1	6	NM_001195528.2	ENSP00000474988.1
TPBGL-AS1	ENST00000530792.1	n.79C>A		non_coding_transcript_exon_variant	Exon 1 of 4	3
TPBGL-AS1	ENST00000603012.1	n.-48C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000218 AC: 33 AN: 151380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000374 AC: 18 AN: 48166 Hom.: 0 AF XY: 0.000346 AC XY: 10 AN XY: 28886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.000433

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000927

Gnomad FIN exome AF: 0.000293

Gnomad NFE exome AF: 0.000585

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000432 AC: 521 AN: 1205972 Hom.: 1 Cov.: 30 AF XY: 0.000406 AC XY: 240 AN XY: 590930

Gnomad4 AFR exome AF: 0.0000408

Gnomad4 AMR exome AF: 0.000654

Gnomad4 ASJ exome AF: 0.000158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.000210

Gnomad4 NFE exome AF: 0.000490

Gnomad4 OTH exome AF: 0.000289

GnomAD4 genome AF: 0.000218 AC: 33 AN: 151488 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 74034

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000485

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000280

ExAC AF: 0.0000888 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>T (p.V16L) alteration is located in exon 1 (coding exon 1) of the TPBGL gene. This alteration results from a G to T substitution at nucleotide position 46, causing the valine (V) at amino acid position 16 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	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.0016	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.033	T
MutationAssessor	Benign	-0.32	N
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.72	T
Vest4		0.054
MVP		0.48
GERP RS		-0.94
Varity_R		0.048
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs540961364; hg19: chr11-74952140;