9-132264459-C-G

Variant names:

• chr9-132264459-C-G
• rs543247171
• NM_015046.7:c.7814G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015046.7(SETX):​c.7814G>C​(p.Arg2605Pro) 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. 17/22 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. R2605Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.518
• Publications: 1 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: Orphanet, Ambry Genetics, 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07521403).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015046.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	NM_015046.7	MANE Select	c.7814G>C	p.Arg2605Pro	missense	Exon 26 of 26	NP_055861.3
	SETX	NM_001351528.2		c.7901G>C	p.Arg2634Pro	missense	Exon 27 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.7814G>C	p.Arg2605Pro	missense	Exon 26 of 26	NP_001338456.1	Q7Z333-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.7814G>C	p.Arg2605Pro	missense	Exon 26 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.7940G>C	p.Arg2647Pro	missense	Exon 28 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.7853G>C	p.Arg2618Pro	missense	Exon 27 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.9
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.52
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.29
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.0	B
Vest4		0.066
MutPred		0.21		Loss of methylation at R2605 (P = 0.0164)
MVP		0.37
MPC		0.11
ClinPred		0.29	T
GERP RS		1.6
Varity_R		0.14
gMVP		0.14
Mutation Taster		=81/19	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: rs543247171; hg19: chr9-135139846;