9-132328287-T-G

Variant names:

• chr9-132328287-T-G
• rs777787438
• NM_015046.7:c.3311A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015046.7(SETX):​c.3311A>C​(p.Gln1104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1104E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.515
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• distal hereditary motor neuropathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11951855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETX	NM_015046.7	c.3311A>C	p.Gln1104Pro	missense_variant	Exon 10 of 26	ENST00000224140.6	NP_055861.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETX	ENST00000224140.6	c.3311A>C	p.Gln1104Pro	missense_variant	Exon 10 of 26	1	NM_015046.7	ENSP00000224140.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461734 Hom.: 0 Cov.: 37 AF XY: 0.00000963 AC XY: 7 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 28, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.0073	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.52
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.36
MutPred		0.19		Gain of loop (P = 0.0079);
MVP		0.68
MPC		0.092
ClinPred		0.38	T
GERP RS		2.7
Varity_R		0.35
gMVP		0.17
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs777787438; hg19: chr9-135203674;