Variant 19-507651-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033513.3(TPGS1):c.145C>T(p.Arg49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,234,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TPGS1
NM_033513.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TPGS1	NM_033513.3 linkuse as main transcript	c.145C>T	p.Arg49Cys	missense_variant	1/2	ENST00000359315.6	NP_277048.2
MADCAM1-AS1	XR_936221.4 linkuse as main transcript	n.239G>A		non_coding_transcript_exon_variant	1/3
MADCAM1-AS1	XR_007067073.1 linkuse as main transcript	n.239G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPGS1	ENST00000359315.6 linkuse as main transcript	c.145C>T	p.Arg49Cys	missense_variant	1/2	1	NM_033513.3	ENSP00000352265	P1	Q6ZTW0-1
MADCAM1-AS1	ENST00000592413.2 linkuse as main transcript	n.183G>A		non_coding_transcript_exon_variant	1/3	5
TPGS1	ENST00000588278.1 linkuse as main transcript	n.152C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1234968

Hom.:

Cov.:

AF XY:

0.0000133

AC XY:

AN XY:

600874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000323

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000403

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000868

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.145C>T (p.R49C) 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 145, causing the arginine (R) at amino acid position 49 to be replaced by a cysteine (C). 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

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

Sift4G

Benign

0.16

Polyphen

0.93

Vest4

0.65

MutPred

0.46

Gain of catalytic residue at M47 (P = 2e-04);

MVP

0.91

MPC

2.0

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.44

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

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