Genetic Variant TPGS1:p.Ala50Val (chr19-507655-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033513.3(TPGS1):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000647 in 1,391,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

TPGS1
NM_033513.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Variant links:

Genes affected

TPGS1 (HGNC:25058): (tubulin polyglutamylase complex subunit 1) Predicted to enable microtubule binding activity. Predicted to be involved in protein polyglutamylation. Predicted to act upstream of or within several processes, including adult behavior; chemical synaptic transmission; and sperm axoneme assembly. Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

TPGS1 links:

MADCAM1-AS1 (HGNC:55315): (MADCAM1 antisense RNA 1)

MADCAM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.103470266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPGS1	NM_033513.3 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	ENST00000359315.6	NP_277048.2	Q6ZTW0-1
MADCAM1-AS1	XR_007067073.1 link	n.235G>A		non_coding_transcript_exon_variant	Exon 1 of 2
MADCAM1-AS1	XR_936221.4 link	n.235G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPGS1	ENST00000359315.6 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	1	NM_033513.3	ENSP00000352265.4	Q6ZTW0-1
TPGS1	ENST00000588278.1 link	n.156C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
MADCAM1-AS1	ENST00000592413.2 link	n.179G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000403

AC:

AN:

1239644

Hom.:

Cov.:

AF XY:

0.00000497

AC XY:

AN XY:

603386

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000107

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000101

Gnomad4 OTH exome

AF:

0.0000201

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000521

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149C>T (p.A50V) alteration is located in exon 1 (coding exon 1) of the TPGS1 gene. This alteration results from a C to T substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by a valine (V). 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

0.19

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.9

REVEL

Benign

0.21

Sift

Benign

0.081

Sift4G

Benign

0.091

Polyphen

0.99

Vest4

0.22

MutPred

0.27

Gain of catalytic residue at A50 (P = 0.0466);

MVP

0.84

MPC

1.0

ClinPred

0.61

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.18

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over