11-75241072-C-G

Variant names:

• chr11-75241072-C-G
• rs1591862534
• NM_001195528.2:c.23C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195528.2(TPBGL):​c.23C>G​(p.Pro8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,140,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TPBGL NM_001195528.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.198

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088617325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPBGL	NM_001195528.2	c.23C>G	p.Pro8Arg	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.23C>G	p.Pro8Arg	missense_variant	Exon 1 of 1	6	NM_001195528.2	ENSP00000474988.1
TPBGL-AS1	ENST00000530792.1	n.102G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3
TPBGL-AS1	ENST00000603012.1	n.-25G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000351 AC: 4 AN: 1140358 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 552582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000397

Gnomad4 SAS exome AF: 0.0000783

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>G (p.P8R) alteration is located in exon 1 (coding exon 1) of the TPBGL gene. This alteration results from a C to G substitution at nucleotide position 23, causing the proline (P) at amino acid position 8 to be replaced by an arginine (R). 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	0.063
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.0071	T
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.089	T
MutationAssessor	Benign	-0.55	N
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.28	T
Vest4		0.24
MVP		0.41
GERP RS		-0.76
Varity_R		0.045
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1591862534; hg19: chr11-74952117;