Genetic Variant NM_033513.3:c.199C>G (chr19-507705-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033513.3. 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
	TPGS1	NM_033513.3	MANE Select	c.199C>G	p.Leu67Val	missense	Exon 1 of 2	NP_277048.2	Q6ZTW0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPGS1	ENST00000359315.6	TSL:1 MANE Select	c.199C>G	p.Leu67Val	missense	Exon 1 of 2	ENSP00000352265.4	Q6ZTW0-1
TPGS1	ENST00000588278.1	TSL:6	n.206C>G		non_coding_transcript_exon	Exon 1 of 1
MADCAM1-AS1	ENST00000592413.2	TSL:5	n.129G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000316

AC:

AN:

63390

AF XY:

0.0000282

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 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

African (AFR)

AF:

0.00

AC:

AN:

24874

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18024

East Asian (EAS)

AF:

0.00

AC:

AN:

28422

South Asian (SAS)

AF:

0.00

AC:

AN:

58896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5010

European-Non Finnish (NFE)

AF:

0.00000300

AC:

AN:

1001030

Other (OTH)

AF:

0.00

AC:

AN:

50390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000172

AC:

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

Uncertain

0.53

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

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

PhyloP100

1.3

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

PromoterAI

-0.063

Neutral

(source)

Varity_R

0.32

gMVP

0.45

Mutation Taster

=64/36

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over