Genetic Variant NM_001195528.2:c.23C>G (chr11-75241072-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.198

Publications

0 publications found

Variant links:

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 links:

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

TPBGL-AS1 links:

ENSG00000308808 (HGNC:):

ENSG00000308808 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.088617325).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195528.2. 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
	TPBGL	NM_001195528.2	MANE Select	c.23C>G	p.Pro8Arg	missense	Exon 1 of 1	NP_001182457.1	P0DKB5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPBGL	ENST00000562197.3	TSL:6 MANE Select	c.23C>G	p.Pro8Arg	missense	Exon 1 of 1	ENSP00000474988.1	P0DKB5
TPBGL-AS1	ENST00000530792.1	TSL:3	n.102G>C		non_coding_transcript_exon	Exon 1 of 4
ENSG00000308808	ENST00000836519.1		n.176-1238G>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000351

AC:

AN:

1140358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

552582

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23030

American (AMR)

AF:

0.00

AC:

AN:

10452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15334

East Asian (EAS)

AF:

0.0000397

AC:

AN:

25214

South Asian (SAS)

AF:

0.0000783

AC:

AN:

38326

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3088

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

954600

Other (OTH)

AF:

0.00

AC:

AN:

45368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00793067), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

0.0032

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0071

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.32

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.089

MutationAssessor

Benign

-0.55

PhyloP100

0.20

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.28

Vest4

0.24

MVP

0.41

GERP RS

-0.76

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.045

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over