3-44243255-G-A

Position:

• chr3-44243255-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145030.2(TOPAZ1):​c.749G>A​(p.Gly250Asp) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOPAZ1 NM_001145030.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.231

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOPAZ1	NM_001145030.2	c.749G>A	p.Gly250Asp	missense_variant	2/20	ENST00000309765.4	NP_001138502.1
TOPAZ1	XM_011533694.3	c.749G>A	p.Gly250Asp	missense_variant	2/20		XP_011531996.1
TOPAZ1	XM_017006361.2	c.749G>A	p.Gly250Asp	missense_variant	2/18		XP_016861850.1
TOPAZ1	XM_017006362.1	c.749G>A	p.Gly250Asp	missense_variant	2/15		XP_016861851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOPAZ1	ENST00000309765.4	c.749G>A	p.Gly250Asp	missense_variant	2/20	5	NM_001145030.2	ENSP00000310303.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Sep 24, 2024

The c.749G>A (p.G250D) alteration is located in exon 2 (coding exon 2) of the TOPAZ1 gene. This alteration results from a G to A substitution at nucleotide position 749, causing the glycine (G) at amino acid position 250 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.2
DANN	Benign	0.69
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.053
Sift	Benign	0.53	T
Sift4G	Benign	0.49	T
Polyphen		0.0040	B
Vest4		0.13
MutPred		0.28		Gain of solvent accessibility (P = 0.0354);
MVP		0.067
ClinPred		0.032	T
GERP RS		-3.2
Varity_R		0.050
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1699509594; hg19: chr3-44284747;