rs2296869

Positions:

• chr9-132297025-A-C
• chr9-132297025-A-G
• chr9-132297025-A-T

Variant summary

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

The NM_015046.7(SETX):​c.5811T>G​(p.Asp1937Glu) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1937D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690

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=0.25001466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.5811T>G	p.Asp1937Glu	missense_variant	14/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.5811T>G	p.Asp1937Glu	missense_variant	14/26	1	NM_015046.7	ENSP00000224140	P1
SETX	ENST00000436441.5	c.537T>G	p.Asp179Glu	missense_variant	4/17	5		ENSP00000409143

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.0081	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.41	.;N
MutationTaster	Benign	0.10	P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.15	T;T
Sift4G	Benign	0.15	T;D
Polyphen		0.23	.;B
Vest4		0.13
MutPred		0.35		.;Gain of ubiquitination at K1940 (P = 0.0719);
MVP		0.52
MPC		0.13
ClinPred		0.22	T
GERP RS		-0.040
Varity_R		0.10
gMVP		0.48

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: rs2296869; hg19: chr9-135172412;