NM_015046.7:c.4660T>G

Variant names:

• chr9-132326938-A-C
• rs112089123
• NM_015046.7:c.4660T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015046.7(SETX):​c.4660T>G​(p.Cys1554Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,614,194 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C1554C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (58 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.92
• Publications: 24 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046750903).
• BP6: Variant 9-132326938-A-C is Benign according to our data. Variant chr9-132326938-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00328 (500/152312) while in subpopulation SAS AF = 0.0242 (117/4826). AF 95% confidence interval is 0.0207. There are 0 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 58 AR,AD gene

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.4660T>G	p.Cys1554Gly	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.4660T>G	p.Cys1554Gly	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.4660T>G	p.Cys1554Gly	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.4660T>G	p.Cys1554Gly	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.4660T>G	p.Cys1554Gly	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.4660T>G	p.Cys1554Gly	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 500 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00549 AC: 1379 AN: 251014 AF XY: 0.00639

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00464 AC: 6779 AN: 1461882 Hom.: 58 Cov.: 33 AF XY: 0.00523 AC XY: 3807 AN XY: 727240

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26134

East Asian (EAS) AF: 0.00484 AC: 192 AN: 39698

South Asian (SAS) AF: 0.0207 AC: 1788 AN: 86258

European-Finnish (FIN) AF: 0.00700 AC: 374 AN: 53414

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00363 AC: 4035 AN: 1112010

Other (OTH) AF: 0.00545 AC: 329 AN: 60396

GnomAD4 genome AF: 0.00328 AC: 500 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00375 AC XY: 279 AN XY: 74476

African (AFR) AF: 0.000674 AC: 28 AN: 41570

American (AMR) AF: 0.000392 AC: 6 AN: 15304

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

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5182

South Asian (SAS) AF: 0.0242 AC: 117 AN: 4826

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00366 AC: 249 AN: 68030

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00214

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00583 AC: 708

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	not specified (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	1	Hereditary spastic paraplegia (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	Uncertain	0.40
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0047	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.9
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.95
MPC		0.11
ClinPred		0.044	T
GERP RS		5.3
Varity_R		0.72
gMVP		0.38
Mutation Taster		=62/38	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: rs112089123; hg19: chr9-135202325; COSMIC: COSV56384208;