rs34073320

Variant names:

• chr9-132283303-C-T
• rs34073320
• NM_015046.7:c.6507G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-132283303-C-T
• chr9-132283303-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015046.7(SETX):​c.6507G>A​(p.Gly2169Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,614,160 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.019 (308 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.915
• Publications: 8 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 9-132283303-C-T is Benign according to our data. Variant chr9-132283303-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.915 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2069/152292) while in subpopulation NFE AF = 0.0219 (1489/68024). AF 95% confidence interval is 0.021. There are 24 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.6507G>A	p.Gly2169Gly	synonymous	Exon 19 of 26	NP_055861.3
	SETX	NM_001351528.2		c.6507G>A	p.Gly2169Gly	synonymous	Exon 19 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.6507G>A	p.Gly2169Gly	synonymous	Exon 19 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.6507G>A	p.Gly2169Gly	synonymous	Exon 19 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.6507G>A	p.Gly2169Gly	synonymous	Exon 19 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.6507G>A	p.Gly2169Gly	synonymous	Exon 19 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2070 AN: 152174 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.0147 AC: 3694 AN: 251484 AF XY: 0.0151

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0193 AC: 28172 AN: 1461868 Hom.: 308 Cov.: 32 AF XY: 0.0191 AC XY: 13861 AN XY: 727232

African (AFR) AF: 0.00299 AC: 100 AN: 33480

American (AMR) AF: 0.00966 AC: 432 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 554 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00443 AC: 382 AN: 86256

European-Finnish (FIN) AF: 0.0105 AC: 559 AN: 53420

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5768

European-Non Finnish (NFE) AF: 0.0224 AC: 24955 AN: 1112000

Other (OTH) AF: 0.0175 AC: 1059 AN: 60392

GnomAD4 genome AF: 0.0136 AC: 2069 AN: 152292 Hom.: 24 Cov.: 32 AF XY: 0.0124 AC XY: 921 AN XY: 74466

African (AFR) AF: 0.00349 AC: 145 AN: 41560

American (AMR) AF: 0.0145 AC: 221 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0219 AC: 1489 AN: 68024

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0168 Hom.: 8

Bravo AF: 0.0131

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0237

EpiControl AF: 0.0220

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Amyotrophic lateral sclerosis type 4 (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
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.2
DANN	Benign	0.83
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs34073320; hg19: chr9-135158690;