3-44243621-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145030.2(TOPAZ1):c.1115C>T(p.Ala372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,397,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000050 (0 hom.)
• Consequence: TOPAZ1 NM_001145030.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 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=0.10099855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOPAZ1	NM_001145030.2	c.1115C>T	p.Ala372Val	missense_variant	2/20	ENST00000309765.4
TOPAZ1	XM_011533694.3	c.1115C>T	p.Ala372Val	missense_variant	2/20
TOPAZ1	XM_017006361.2	c.1115C>T	p.Ala372Val	missense_variant	2/18
TOPAZ1	XM_017006362.1	c.1115C>T	p.Ala372Val	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOPAZ1	ENST00000309765.4	c.1115C>T	p.Ala372Val	missense_variant	2/20	5	NM_001145030.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000501 AC: 7 AN: 1397850 Hom.: 0 Cov.: 34 AF XY: 0.00000290 AC XY: 2 AN XY: 689446

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: 0.00000556

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The c.1115C>T (p.A372V) alteration is located in exon 2 (coding exon 2) of the TOPAZ1 gene. This alteration results from a C to T substitution at nucleotide position 1115, causing the alanine (A) at amino acid position 372 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	Benign	0.094
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.058
Sift	Benign	0.052	T
Sift4G	Benign	0.095	T
Polyphen		0.57	P
Vest4		0.095
MutPred		0.26		Gain of sheet (P = 0.0043);
MVP		0.067
ClinPred		0.45	T
GERP RS		3.6
Varity_R		0.048
gMVP		0.036

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.

Other links and lift over

hg19: chr3-44285113;