3-44243299-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001145030.2(TOPAZ1):c.793C>T(p.Leu265Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,551,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

TOPAZ1
NM_001145030.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00600

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007701069).

BP6

Variant 3-44243299-C-T is Benign according to our data. Variant chr3-44243299-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2338447.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TOPAZ1	NM_001145030.2 linkuse as main transcript	c.793C>T	p.Leu265Phe	missense_variant	2/20	ENST00000309765.4
TOPAZ1	XM_011533694.3 linkuse as main transcript	c.793C>T	p.Leu265Phe	missense_variant	2/20
TOPAZ1	XM_017006361.2 linkuse as main transcript	c.793C>T	p.Leu265Phe	missense_variant	2/18
TOPAZ1	XM_017006362.1 linkuse as main transcript	c.793C>T	p.Leu265Phe	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOPAZ1	ENST00000309765.4 linkuse as main transcript	c.793C>T	p.Leu265Phe	missense_variant	2/20	5	NM_001145030.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000533

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000417

AC:

AN:

155972

Hom.:

AF XY:

0.000387

AC XY:

AN XY:

82774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000447

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000119

Gnomad NFE exome

AF:

0.000813

Gnomad OTH exome

AF:

0.000685

GnomAD4 exome

AF:

0.000669

AC:

936

AN:

1399218

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

445

AN XY:

690104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.000420

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000305

Gnomad4 NFE exome

AF:

0.000809

Gnomad4 OTH exome

AF:

0.000535

GnomAD4 genome

AF:

0.000532

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000664

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000327

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.77

Cadd

Benign

5.2

Dann

Benign

0.44

DEOGEN2

Benign

0.0057

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.45

M_CAP

Benign

0.0027

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.97

REVEL

Benign

0.022

Sift

Benign

0.31

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.062

MVP

0.014

ClinPred

0.056

GERP RS

-0.16

Varity_R

0.057

gMVP

0.042

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