rs1183768

Variant names:

• chr9-132327844-C-T
• rs1183768
• NM_015046.7:c.3754G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001351528.2(SETX):​c.3754G>A​(p.Gly1252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,613,874 control chromosomes in the GnomAD database, including 520,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38858 hom., cov: 31)
  • Exomes 𝑓: 0.80 (481992 hom.)
• Consequence: SETX NM_001351528.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.508
• Publications: 42 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.695825E-7).
• BP6: Variant 9-132327844-C-T is Benign according to our data. Variant chr9-132327844-C-T is described in ClinVar as Benign. ClinVar VariationId is 95662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351528.2. 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.3754G>A	p.Gly1252Arg	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3754G>A	p.Gly1252Arg	missense	Exon 10 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.3754G>A	p.Gly1252Arg	missense	Exon 10 of 26	NP_001338456.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETX	ENST00000224140.6	TSL:1 MANE Select	c.3754G>A	p.Gly1252Arg	missense	Exon 10 of 26	ENSP00000224140.5
	SETX	ENST00000923216.1		c.3754G>A	p.Gly1252Arg	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3754G>A	p.Gly1252Arg	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103831 AN: 151922 Hom.: 38853 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.860

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.728

GnomAD2 exomes AF: 0.734 AC: 184546 AN: 251284 AF XY: 0.740

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.748

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.842

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.802 AC: 1172479 AN: 1461834 Hom.: 481992 Cov.: 70 AF XY: 0.798 AC XY: 580592 AN XY: 727216

African (AFR) AF: 0.368 AC: 12328 AN: 33480

American (AMR) AF: 0.794 AC: 35508 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 19517 AN: 26134

East Asian (EAS) AF: 0.287 AC: 11406 AN: 39698

South Asian (SAS) AF: 0.637 AC: 54983 AN: 86256

European-Finnish (FIN) AF: 0.831 AC: 44406 AN: 53406

Middle Eastern (MID) AF: 0.662 AC: 3816 AN: 5768

European-Non Finnish (NFE) AF: 0.850 AC: 944827 AN: 1111972

Other (OTH) AF: 0.756 AC: 45688 AN: 60396

GnomAD4 genome AF: 0.683 AC: 103853 AN: 152040 Hom.: 38858 Cov.: 31 AF XY: 0.681 AC XY: 50590 AN XY: 74300

African (AFR) AF: 0.384 AC: 15921 AN: 41446

American (AMR) AF: 0.787 AC: 11998 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2550 AN: 3472

East Asian (EAS) AF: 0.324 AC: 1671 AN: 5160

South Asian (SAS) AF: 0.620 AC: 2987 AN: 4816

European-Finnish (FIN) AF: 0.832 AC: 8798 AN: 10576

Middle Eastern (MID) AF: 0.699 AC: 204 AN: 292

European-Non Finnish (NFE) AF: 0.844 AC: 57410 AN: 68008

Other (OTH) AF: 0.727 AC: 1533 AN: 2108

Alfa AF: 0.779 Hom.: 182779

Bravo AF: 0.665

TwinsUK AF: 0.855 AC: 3172

ALSPAC AF: 0.842 AC: 3244

ESP6500AA AF: 0.397 AC: 1747

ESP6500EA AF: 0.845 AC: 7267

ExAC AF: 0.725 AC: 88015

Asia WGS AF: 0.492 AC: 1713 AN: 3478

EpiCase AF: 0.840

EpiControl AF: 0.834

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	Amyotrophic lateral sclerosis type 4 (3)
-	-	3	not provided (3)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	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	0.25
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.51
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.24
Sift	Benign	0.13	T
Sift4G	Benign	0.46	T
Polyphen		0.48	P
Vest4		0.28
MutPred		0.14		Gain of helix (P = 0.0696)
MPC		0.099
ClinPred		0.020	T
GERP RS		4.7
Varity_R		0.072
gMVP		0.14
Mutation Taster		=58/42	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: rs1183768; hg19: chr9-135203231; COSMIC: COSV56379133;