rs3739921

Variant names:

• chr9-132328451-G-A
• rs3739921
• NM_015046.7:c.3147C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015046.7(SETX):​c.3147C>T​(p.His1049His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,613,326 control chromosomes in the GnomAD database, including 8,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (635 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7697 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.44
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-132328451-G-A is Benign according to our data. Variant chr9-132328451-G-A is described in ClinVar as Benign. ClinVar VariationId is 193716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.225 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.3147C>T	p.His1049His	synonymous	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.3147C>T	p.His1049His	synonymous	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.3147C>T	p.His1049His	synonymous	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.3147C>T	p.His1049His	synonymous	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.3147C>T	p.His1049His	synonymous	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.3147C>T	p.His1049His	synonymous	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12418 AN: 151908 Hom.: 637 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.0804

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.0828

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0806

Gnomad OTH AF: 0.0901

GnomAD2 exomes AF: 0.108 AC: 27065 AN: 250960 AF XY: 0.113

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.0822

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0924 AC: 134961 AN: 1461300 Hom.: 7697 Cov.: 37 AF XY: 0.0962 AC XY: 69966 AN XY: 726964

African (AFR) AF: 0.0433 AC: 1449 AN: 33460

American (AMR) AF: 0.0885 AC: 3954 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3367 AN: 26122

East Asian (EAS) AF: 0.257 AC: 10198 AN: 39680

South Asian (SAS) AF: 0.201 AC: 17307 AN: 86224

European-Finnish (FIN) AF: 0.0774 AC: 4115 AN: 53132

Middle Eastern (MID) AF: 0.178 AC: 1028 AN: 5764

European-Non Finnish (NFE) AF: 0.0786 AC: 87383 AN: 1111850

Other (OTH) AF: 0.102 AC: 6160 AN: 60378

GnomAD4 genome AF: 0.0818 AC: 12430 AN: 152026 Hom.: 635 Cov.: 32 AF XY: 0.0859 AC XY: 6378 AN XY: 74278

African (AFR) AF: 0.0434 AC: 1797 AN: 41446

American (AMR) AF: 0.0853 AC: 1303 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3464

East Asian (EAS) AF: 0.236 AC: 1222 AN: 5172

South Asian (SAS) AF: 0.202 AC: 972 AN: 4812

European-Finnish (FIN) AF: 0.0828 AC: 874 AN: 10558

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0806 AC: 5479 AN: 67988

Other (OTH) AF: 0.0920 AC: 194 AN: 2108

Alfa AF: 0.0818 Hom.: 870

Bravo AF: 0.0801

Asia WGS AF: 0.193 AC: 670 AN: 3478

EpiCase AF: 0.0838

EpiControl AF: 0.0883

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.37
DANN	Benign	0.29
PhyloP100		-1.4
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: rs3739921; hg19: chr9-135203838; COSMIC: COSV56383870;