rs113856732

Positions:

• chr9-132327381-G-C
• chr9-132327381-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015046.7(SETX):​c.4217C>G​(p.Ala1406Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1839684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETX	NM_015046.7	c.4217C>G	p.Ala1406Gly	missense_variant	10/26	ENST00000224140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETX	ENST00000224140.6	c.4217C>G	p.Ala1406Gly	missense_variant	10/26	1	NM_015046.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

May 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.0069
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Uncertain	0.012	D
Sift4G	Benign	0.19	T
Polyphen		0.92	P
Vest4		0.096
MutPred		0.17		Loss of stability (P = 0.0387);
MVP		0.81
MPC		0.079
ClinPred		0.49	T
GERP RS		5.5
Varity_R		0.084
gMVP		0.13

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: rs113856732; hg19: chr9-135202768;