rs1554809388

Positions:

• chr9-132288646-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000224140.6(SETX):​c.6112T>C​(p.Cys2038Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETX ENST00000224140.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETX	NM_015046.7	c.6112T>C	p.Cys2038Arg	missense_variant	16/26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.6112T>C	p.Cys2038Arg	missense_variant	16/26	1	NM_015046.7	ENSP00000224140	P1
SETX	ENST00000436441.5	c.838T>C	p.Cys280Arg	missense_variant	6/17	5		ENSP00000409143

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Athena Diagnostics

Dec 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.18	T;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.78
MutPred		0.59		.;Gain of disorder (P = 0.023);
MVP		0.84
MPC		0.57
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.92

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: rs1554809388; hg19: chr9-135164033;