rs9284879

chr3-44243092-G-Achr3-44243092-G-Cchr3-44243092-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145030.2(TOPAZ1):c.586G>A(p.Val196Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,546,734 control chromosomes in the GnomAD database, including 197,564 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.46 (17414 hom., cov: 33)
  • Exomes 𝑓: 0.50 (180150 hom.)
• Consequence: TOPAZ1 NM_001145030.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.056289E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOPAZ1	NM_001145030.2	c.586G>A	p.Val196Ile	missense_variant	2/20	ENST00000309765.4
TOPAZ1	XM_011533694.3	c.586G>A	p.Val196Ile	missense_variant	2/20
TOPAZ1	XM_017006361.2	c.586G>A	p.Val196Ile	missense_variant	2/18
TOPAZ1	XM_017006362.1	c.586G>A	p.Val196Ile	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOPAZ1	ENST00000309765.4	c.586G>A	p.Val196Ile	missense_variant	2/20	5	NM_001145030.2	P1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70098 AN: 151910 Hom.: 17403 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.554 AC: 85047 AN: 153438 Hom.: 24660 AF XY: 0.561 AC XY: 45556 AN XY: 81216

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.808

Gnomad SAS exome AF: 0.687

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.501 AC: 699148 AN: 1394706 Hom.: 180150 Cov.: 39 AF XY: 0.507 AC XY: 348269 AN XY: 687196

Gnomad4 AFR exome AF: 0.307

Gnomad4 AMR exome AF: 0.601

Gnomad4 ASJ exome AF: 0.529

Gnomad4 EAS exome AF: 0.829

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.461 AC: 70141 AN: 152028 Hom.: 17414 Cov.: 33 AF XY: 0.471 AC XY: 35025 AN XY: 74306

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.538

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.704

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.477

Gnomad4 OTH AF: 0.460

Alfa AF: 0.487 Hom.: 45911

Bravo AF: 0.453

TwinsUK AF: 0.481 AC: 1784

ALSPAC AF: 0.465 AC: 1794

ESP6500AA AF: 0.306 AC: 423

ESP6500EA AF: 0.469 AC: 1488

ExAC AF: 0.532 AC: 12332

Asia WGS AF: 0.718 AC: 2498 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.032
Sift	Uncertain	0.017	D
Sift4G	Benign	0.084	T
Polyphen		0.021	B
Vest4		0.030
ClinPred		0.0070	T
GERP RS		3.0
Varity_R		0.045
gMVP		0.066

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

Other links and lift over

dbSNP: rs9284879; hg19: chr3-44284584; COSMIC: COSV59068033;