rs139063885

Variant names:

• chr9-132311848-T-C
• rs139063885
• NM_015046.7:c.5283A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001351528.2(SETX):​c.5283A>G​(p.Gln1761Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,611,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: SETX NM_001351528.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.379
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-132311848-T-C is Benign according to our data. Variant chr9-132311848-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365351.
• BP7: Synonymous conserved (PhyloP=0.379 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000534 (779/1459700) while in subpopulation MID AF = 0.00139 (8/5760). AF 95% confidence interval is 0.000691. There are 0 homozygotes in GnomAdExome4. There are 374 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.5283A>G	p.Gln1761Gln	synonymous	Exon 11 of 26	NP_055861.3
	SETX	NM_001351528.2		c.5283A>G	p.Gln1761Gln	synonymous	Exon 11 of 27	NP_001338457.1
	SETX	NM_001351527.2		c.5283A>G	p.Gln1761Gln	synonymous	Exon 11 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.5283A>G	p.Gln1761Gln	synonymous	Exon 11 of 26	ENSP00000224140.5
	SETX	ENST00000923216.1		c.5283A>G	p.Gln1761Gln	synonymous	Exon 11 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.5283A>G	p.Gln1761Gln	synonymous	Exon 11 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 250608 AF XY: 0.000317

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000534 AC: 779 AN: 1459700 Hom.: 0 Cov.: 30 AF XY: 0.000515 AC XY: 374 AN XY: 726244

African (AFR) AF: 0.000120 AC: 4 AN: 33418

American (AMR) AF: 0.0000671 AC: 3 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.000637 AC: 707 AN: 1110482

Other (OTH) AF: 0.000696 AC: 42 AN: 60328

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74378

African (AFR) AF: 0.000265 AC: 11 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000609 Hom.: 0

Bravo AF: 0.000359

EpiCase AF: 0.000327

EpiControl AF: 0.000416

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amyotrophic lateral sclerosis type 4 (1)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	not specified (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	-0.62
CADD	Benign	8.7
DANN	Benign	0.64
PhyloP100		0.38
PromoterAI		-0.0018	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139063885; hg19: chr9-135187235;