9-132264514-T-G

Position:

• chr9-132264514-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015046.7(SETX):​c.7759A>C​(p.Ile2587Leu) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2587V) 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: -1.19

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]

SETX (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050157577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.7759A>C	p.Ile2587Leu	missense_variant	26/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.7759A>C	p.Ile2587Leu	missense_variant	26/26	1	NM_015046.7	ENSP00000224140.5
SETX	ENST00000436441.5	c.2572A>C	p.Ile858Leu	missense_variant	17/17	5		ENSP00000409143.1
SETX	ENST00000477049.1	n.909A>C		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.019
DANN	Benign	0.75
DEOGEN2	Benign	0.10	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.14	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.34	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.18
Sift	Benign	0.29	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0	.;B
Vest4		0.11
MutPred		0.14		.;Gain of relative solvent accessibility (P = 0.1571);
MVP		0.37
MPC		0.074
ClinPred		0.060	T
GERP RS		-3.8
Varity_R		0.034
gMVP		0.078

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: rs1056899; hg19: chr9-135139901;