NM_015046.7:c.1391C>T

Variant names:

• chr9-132330207-G-A
• rs200614765
• NM_015046.7:c.1391C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS1

The NM_015046.7(SETX):​c.1391C>T​(p.Ser464Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00048 in 1,572,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S464S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 4.80
• Publications: 6 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00051 (724/1420108) while in subpopulation NFE AF = 0.00065 (709/1090982). AF 95% confidence interval is 0.00061. There are 0 homozygotes in GnomAdExome4. There are 359 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

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.1391C>T	p.Ser464Leu	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.1391C>T	p.Ser464Leu	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.1391C>T	p.Ser464Leu	missense	Exon 10 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.1391C>T	p.Ser464Leu	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.1391C>T	p.Ser464Leu	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.1391C>T	p.Ser464Leu	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 30 AN: 219014 AF XY: 0.000111

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.000581

GnomAD4 exome AF: 0.000510 AC: 724 AN: 1420108 Hom.: 0 Cov.: 35 AF XY: 0.000512 AC XY: 359 AN XY: 701546

African (AFR) AF: 0.000187 AC: 6 AN: 32002

American (AMR) AF: 0.00 AC: 0 AN: 39122

Ashkenazi Jewish (ASJ) AF: 0.0000425 AC: 1 AN: 23508

East Asian (EAS) AF: 0.00 AC: 0 AN: 39224

South Asian (SAS) AF: 0.00 AC: 0 AN: 79390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.000650 AC: 709 AN: 1090982

Other (OTH) AF: 0.000137 AC: 8 AN: 58428

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74330

African (AFR) AF: 0.000169 AC: 7 AN: 41446

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000148 AC: 18

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Amyotrophic lateral sclerosis type 4 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	SETX-related disorder (1)
-	1	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.88
MPC		0.41
ClinPred		0.14	T
GERP RS		5.7
Varity_R		0.28
gMVP		0.59
Mutation Taster		=4/96	disease causing

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: rs200614765; hg19: chr9-135205594;