3-44242376-T-G

Position:

• chr3-44242376-T-G

Variant summary

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

The NM_001145030.2(TOPAZ1):​c.323T>G​(p.Leu108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TOPAZ1 NM_001145030.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.394

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=0.119457334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOPAZ1	NM_001145030.2	c.323T>G	p.Leu108Arg	missense_variant	1/20	ENST00000309765.4	NP_001138502.1
TOPAZ1	XM_011533694.3	c.323T>G	p.Leu108Arg	missense_variant	1/20		XP_011531996.1
TOPAZ1	XM_017006361.2	c.323T>G	p.Leu108Arg	missense_variant	1/18		XP_016861850.1
TOPAZ1	XM_017006362.1	c.323T>G	p.Leu108Arg	missense_variant	1/15		XP_016861851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOPAZ1	ENST00000309765.4	c.323T>G	p.Leu108Arg	missense_variant	1/20	5	NM_001145030.2	ENSP00000310303.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

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

Jun 16, 2023

The c.323T>G (p.L108R) alteration is located in exon 1 (coding exon 1) of the TOPAZ1 gene. This alteration results from a T to G substitution at nucleotide position 323, causing the leucine (L) at amino acid position 108 to be replaced by an arginine (R). 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	0.081
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.057
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.054	T
Polyphen		0.81	P
Vest4		0.31
MutPred		0.15		Gain of MoRF binding (P = 0.0177);
MVP		0.12
ClinPred		0.22	T
GERP RS		1.1
Varity_R		0.093
gMVP		0.13

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: chr3-44283868;