chr9-132327442-T-C

Variant names:

• chr9-132327442-T-C
• rs543573
• NM_015046.7:c.4156A>G

Variant summary

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

The NM_015046.7(SETX):​c.4156A>G​(p.Ile1386Val) 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 1,613,932 control chromosomes in the GnomAD database, including 520,902 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1386L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (38890 hom., cov: 32)
  • Exomes 𝑓: 0.80 (482012 hom.)
• Consequence: SETX NM_015046.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.06
• Publications: 50 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=8.7603087E-7).
• BP6: Variant 9-132327442-T-C is Benign according to our data. Variant chr9-132327442-T-C is described in ClinVar as Benign. ClinVar VariationId is 95663.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_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.4156A>G	p.Ile1386Val	missense	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.4156A>G	p.Ile1386Val	missense	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.4156A>G	p.Ile1386Val	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.4156A>G	p.Ile1386Val	missense	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.4156A>G	p.Ile1386Val	missense	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.4156A>G	p.Ile1386Val	missense	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103914 AN: 152054 Hom.: 38885 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.727

GnomAD2 exomes AF: 0.734 AC: 184658 AN: 251408 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: 0.777

GnomAD4 exome AF: 0.802 AC: 1172476 AN: 1461760 Hom.: 482012 Cov.: 60 AF XY: 0.798 AC XY: 580592 AN XY: 727182

African (AFR) AF: 0.368 AC: 12325 AN: 33476

American (AMR) AF: 0.794 AC: 35513 AN: 44724

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

East Asian (EAS) AF: 0.287 AC: 11410 AN: 39696

South Asian (SAS) AF: 0.637 AC: 54983 AN: 86248

European-Finnish (FIN) AF: 0.832 AC: 44392 AN: 53380

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

European-Non Finnish (NFE) AF: 0.850 AC: 944831 AN: 1111940

Other (OTH) AF: 0.757 AC: 45689 AN: 60394

GnomAD4 genome AF: 0.683 AC: 103936 AN: 152172 Hom.: 38890 Cov.: 32 AF XY: 0.681 AC XY: 50637 AN XY: 74390

African (AFR) AF: 0.384 AC: 15924 AN: 41464

American (AMR) AF: 0.786 AC: 12019 AN: 15282

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

East Asian (EAS) AF: 0.324 AC: 1678 AN: 5184

South Asian (SAS) AF: 0.620 AC: 2993 AN: 4828

European-Finnish (FIN) AF: 0.832 AC: 8815 AN: 10592

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57434 AN: 68030

Other (OTH) AF: 0.726 AC: 1534 AN: 2114

Alfa AF: 0.782 Hom.: 163366

Bravo AF: 0.665

TwinsUK AF: 0.855 AC: 3172

ALSPAC AF: 0.842 AC: 3244

ESP6500AA AF: 0.397 AC: 1750

ESP6500EA AF: 0.846 AC: 7273

ExAC AF: 0.725 AC: 88023

Asia WGS AF: 0.493 AC: 1714 AN: 3478

EpiCase AF: 0.840

EpiControl AF: 0.834

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	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	0.072
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.0030
DANN	Benign	0.16
DEOGEN2	Benign	0.088	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.038	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.1
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.25
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.063
ClinPred		0.0019	T
GERP RS		-1.6
Varity_R		0.011
gMVP		0.083
Mutation Taster		=100/0	polymorphism (auto)

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: rs543573; hg19: chr9-135202829; COSMIC: COSV56379117;