rs3739927

chr9-132264439-T-Achr9-132264439-T-Cchr9-132264439-T-G

Variant summary

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

The NM_015046.7(SETX):c.7834A>T(p.Ser2612Cys) 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. 12/20 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. S2612G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45

Genes affected

SETX (HGNC:445): (senataxin) This gene encodes a protein named for its homology to the Sen1p protein of fungi which has RNA helicase activity encoded by a domain at the C-terminal end of the protein. The protein encoded by this gene contains a DNA/RNA helicase domain at its C-terminal end which suggests that it may be involved in both DNA and RNA processing. Mutations in this gene have been associated with ataxia-ocular apraxia-2 (AOA2) and an autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS4). [provided by RefSeq, Jul 2008]

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=0.18963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.7834A>T	p.Ser2612Cys	missense_variant	26/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.7834A>T	p.Ser2612Cys	missense_variant	26/26	1	NM_015046.7	P1
SETX	ENST00000436441.5	c.2647A>T	p.Ser883Cys	missense_variant	17/17	5
SETX	ENST00000477049.1	n.984A>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	11
Dann	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	-0.034	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.046	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.97	.;D
Vest4		0.11
MutPred		0.13		.;Loss of phosphorylation at S2612 (P = 0.0115);
MVP		0.74
MPC		0.30
ClinPred		0.86	D
GERP RS		-4.6
Varity_R		0.058
gMVP		0.18

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: rs3739927; hg19: chr9-135139826;