10-68827818-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_152709.5(STOX1):c.195G>C(p.Trp65Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: STOX1 NM_152709.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

STOX1 (HGNC:23508): (storkhead box 1) Enables RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in several processes, including positive regulation of G2/M transition of mitotic cell cycle; positive regulation of protein phosphorylation; and regulation of gene expression. Located in centrosome; cytosol; and nuclear lumen. Implicated in pre-eclampsia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STOX1	NM_152709.5	c.195G>C	p.Trp65Cys	missense_variant	1/4	ENST00000298596.11
STOX1	NM_001130161.4	c.195G>C	p.Trp65Cys	missense_variant	1/5
STOX1	NM_001130159.3	c.195G>C	p.Trp65Cys	missense_variant	1/4
STOX1	NM_001130160.3	c.195G>C	p.Trp65Cys	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STOX1	ENST00000298596.11	c.195G>C	p.Trp65Cys	missense_variant	1/4	1	NM_152709.5	P4

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 10

Bravo AF: 0.00000378

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

Nov 19, 2022

The c.195G>C (p.W65C) alteration is located in exon 1 (coding exon 1) of the STOX1 gene. This alteration results from a G to C substitution at nucleotide position 195, causing the tryptophan (W) at amino acid position 65 to be replaced by a cysteine (C). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.082	T;T;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.5	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Pathogenic	-4.8	D;D;.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.50
MutPred		0.67		Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);
MVP		0.72
MPC		0.52
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.42

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: rs1387182769; hg19: chr10-70587575;