rs35815657

Variant names:

• chr9-132288650-T-C
• rs35815657
• NM_015046.7:c.6108A>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.6108A>G​(p.Gly2036Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,602,914 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: SETX NM_015046.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.0006551
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.395
• Publications: 2 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=-0.44).
• BP6: Variant 9-132288650-T-C is Benign according to our data. Variant chr9-132288650-T-C is described in ClinVar as Benign. ClinVar VariationId is 536402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.395 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00324 (494/152332) while in subpopulation AFR AF = 0.0113 (470/41570). AF 95% confidence interval is 0.0105. There are 4 homozygotes in GnomAd4. There are 232 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.6108A>G	p.Gly2036Gly	splice_region synonymous	Exon 16 of 26	NP_055861.3
	SETX	NM_001351528.2		c.6108A>G	p.Gly2036Gly	splice_region synonymous	Exon 16 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.6108A>G	p.Gly2036Gly	splice_region synonymous	Exon 16 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.6108A>G	p.Gly2036Gly	splice_region synonymous	Exon 16 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.6108A>G	p.Gly2036Gly	splice_region synonymous	Exon 16 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.6108A>G	p.Gly2036Gly	splice_region synonymous	Exon 16 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 489 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000718 AC: 180 AN: 250550 AF XY: 0.000502

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000299 AC: 434 AN: 1450582 Hom.: 0 Cov.: 28 AF XY: 0.000263 AC XY: 190 AN XY: 722462

African (AFR) AF: 0.0112 AC: 372 AN: 33238

American (AMR) AF: 0.000515 AC: 23 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1102016

Other (OTH) AF: 0.000583 AC: 35 AN: 60006

GnomAD4 genome AF: 0.00324 AC: 494 AN: 152332 Hom.: 4 Cov.: 32 AF XY: 0.00311 AC XY: 232 AN XY: 74504

African (AFR) AF: 0.0113 AC: 470 AN: 41570

American (AMR) AF: 0.000980 AC: 15 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00121 Hom.: 2

Bravo AF: 0.00336

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	1	Amyotrophic lateral sclerosis type 4 (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
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		0.40
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.040		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: rs35815657; hg19: chr9-135164037;