chr3-44243092-G-C

Variant names:

• chr3-44243092-G-C
• rs9284879
• NM_001145030.2:c.586G>C

Variant summary

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

The NM_001145030.2(TOPAZ1):​c.586G>C​(p.Val196Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V196I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• 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 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=0.09577626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPAZ1	NM_001145030.2	c.586G>C	p.Val196Leu	missense_variant	Exon 2 of 20	ENST00000309765.4	NP_001138502.1
TOPAZ1	XM_011533694.3	c.586G>C	p.Val196Leu	missense_variant	Exon 2 of 20		XP_011531996.1
TOPAZ1	XM_017006361.2	c.586G>C	p.Val196Leu	missense_variant	Exon 2 of 18		XP_016861850.1
TOPAZ1	XM_017006362.1	c.586G>C	p.Val196Leu	missense_variant	Exon 2 of 15		XP_016861851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOPAZ1	ENST00000309765.4	c.586G>C	p.Val196Leu	missense_variant	Exon 2 of 20	5	NM_001145030.2	ENSP00000310303.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.027
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.059	T
Polyphen		0.59	P
Vest4		0.26
MutPred		0.23		Gain of helix (P = 0.0199);
MVP		0.076
ClinPred		0.26	T
GERP RS		3.0
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

LitVar

Other links and lift over

dbSNP: rs9284879; hg19: chr3-44284584;