10-68827727-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152709.5(STOX1):c.104C>T(p.Ala35Val) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STOX1 NM_152709.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31495684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STOX1	NM_152709.5	c.104C>T	p.Ala35Val	missense_variant	1/4	ENST00000298596.11
STOX1	NM_001130161.4	c.104C>T	p.Ala35Val	missense_variant	1/5
STOX1	NM_001130159.3	c.104C>T	p.Ala35Val	missense_variant	1/4
STOX1	NM_001130160.3	c.104C>T	p.Ala35Val	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STOX1	ENST00000298596.11	c.104C>T	p.Ala35Val	missense_variant	1/4	1	NM_152709.5	P4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000140 AC: 1 AN: 712266 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 337602

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: 0.00000160

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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 14, 2022

The c.104C>T (p.A35V) alteration is located in exon 1 (coding exon 1) of the STOX1 gene. This alteration results from a C to T substitution at nucleotide position 104, causing the alanine (A) at amino acid position 35 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	0.29
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0090	T;T;.;.;.
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.42	N
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.9	L;L;.;L;L
MutationTaster	Benign	0.99	N;N;N;N
PROVEAN	Benign	-0.72	N;N;.;N;N
REVEL	Benign	0.27
Sift	Benign	0.26	T;T;.;T;T
Sift4G	Benign	0.21	T;T;.;T;T
Polyphen		0.99	D;D;.;P;P
Vest4		0.26
MutPred		0.41		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP		0.67
MPC		0.19
ClinPred		0.70	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.077

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: chr10-70587484;