Variant chr3-44243505-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001145030.2(TOPAZ1):c.999G>C(p.Arg333Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 7.1e-7 ( 0 hom. )

Consequence

TOPAZ1
NM_001145030.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.16

Variant links:

Genes affected

TOPAZ1 (HGNC:24746): (testis and ovary specific TOPAZ 1) Predicted to be involved in spermatid development and spermatocyte division. Predicted to act upstream of or within apoptotic process; ncRNA transcription; and positive regulation of meiotic cell cycle phase transition. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TOPAZ1 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=0.09862724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TOPAZ1	NM_001145030.2 linkuse as main transcript	c.999G>C	p.Arg333Ser	missense_variant	2/20	ENST00000309765.4
TOPAZ1	XM_011533694.3 linkuse as main transcript	c.999G>C	p.Arg333Ser	missense_variant	2/20
TOPAZ1	XM_017006361.2 linkuse as main transcript	c.999G>C	p.Arg333Ser	missense_variant	2/18
TOPAZ1	XM_017006362.1 linkuse as main transcript	c.999G>C	p.Arg333Ser	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOPAZ1	ENST00000309765.4 linkuse as main transcript	c.999G>C	p.Arg333Ser	missense_variant	2/20	5	NM_001145030.2	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690180

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Nov 07, 2022

The c.999G>C (p.R333S) alteration is located in exon 2 (coding exon 2) of the TOPAZ1 gene. This alteration results from a G to C substitution at nucleotide position 999, causing the arginine (R) at amino acid position 333 to be replaced by a serine (S). 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

0.49

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.049

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

M_CAP

Benign

0.015

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.99

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.065

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.023

Polyphen

0.76

Vest4

0.13

MutPred

0.29

Gain of phosphorylation at R333 (P = 0.002);

MVP

0.014

ClinPred

0.46

GERP RS

3.7

Varity_R

0.20

gMVP

0.12

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over