Genetic Variant TPGS1:p.Leu67Val (chr19-507705-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_033513.3(TPGS1):c.199C>G(p.Leu67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 1,245,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

TPGS1
NM_033513.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.28

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPGS1	NM_033513.3 link	c.199C>G	p.Leu67Val	missense_variant	Exon 1 of 2	ENST00000359315.6	NP_277048.2	Q6ZTW0-1
MADCAM1-AS1	XR_007067073.1 link	n.185G>C		non_coding_transcript_exon_variant	Exon 1 of 2
MADCAM1-AS1	XR_936221.4 link	n.185G>C		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.199C>G	p.Leu67Val	missense_variant	Exon 1 of 2	1	NM_033513.3	ENSP00000352265.4	Q6ZTW0-1
TPGS1	ENST00000588278.1 link	n.206C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MADCAM1-AS1	ENST00000592413.2 link	n.129G>C		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000316

AC:

AN:

63390

Hom.:

AF XY:

0.0000282

AC XY:

AN XY:

35430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000653

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000241

AC:

AN:

1245324

Hom.:

Cov.:

AF XY:

0.00000331

AC XY:

AN XY:

605042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000300

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000172

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>G (p.L67V) alteration is located in exon 1 (coding exon 1) of the TPGS1 gene. This alteration results from a C to G substitution at nucleotide position 199, causing the leucine (L) at amino acid position 67 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

Uncertain

0.53

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

0.15

Eigen_PC

Benign

0.067

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.2

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.59

MutPred

0.56

Gain of catalytic residue at L67 (P = 0.1561);

MVP

0.46

MPC

2.0

ClinPred

0.89

GERP RS

0.79

Varity_R

0.32

gMVP

0.45

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