NM_015046.7:c.4755T>G

Variant names:

• chr9-132326843-A-C
• rs151237267
• NM_015046.7:c.4755T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015046.7(SETX):​c.4755T>G​(p.Pro1585Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,614,212 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (72 hom.)
• Consequence: SETX NM_015046.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.09
• Publications: 4 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=-0.88).
• BP6: Variant 9-132326843-A-C is Benign according to our data. Variant chr9-132326843-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00517 (788/152328) while in subpopulation SAS AF = 0.0135 (65/4818). AF 95% confidence interval is 0.0109. There are 3 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.4755T>G	p.Pro1585Pro	synonymous	Exon 10 of 26	NP_055861.3
	SETX	NM_001351528.2		c.4755T>G	p.Pro1585Pro	synonymous	Exon 10 of 27	NP_001338457.1	Q7Z333-4
	SETX	NM_001351527.2		c.4755T>G	p.Pro1585Pro	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.4755T>G	p.Pro1585Pro	synonymous	Exon 10 of 26	ENSP00000224140.5	Q7Z333-1
	SETX	ENST00000923216.1		c.4755T>G	p.Pro1585Pro	synonymous	Exon 10 of 28	ENSP00000593275.1
	SETX	ENST00000923217.1		c.4755T>G	p.Pro1585Pro	synonymous	Exon 10 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00610 AC: 1534 AN: 251378 AF XY: 0.00681

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00740 AC: 10821 AN: 1461884 Hom.: 72 Cov.: 33 AF XY: 0.00770 AC XY: 5602 AN XY: 727242

African (AFR) AF: 0.00191 AC: 64 AN: 33480

American (AMR) AF: 0.00456 AC: 204 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 447 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.0122 AC: 1052 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53418

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5768

European-Non Finnish (NFE) AF: 0.00766 AC: 8514 AN: 1112008

Other (OTH) AF: 0.00709 AC: 428 AN: 60396

GnomAD4 genome AF: 0.00517 AC: 788 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74500

African (AFR) AF: 0.00214 AC: 89 AN: 41570

American (AMR) AF: 0.00529 AC: 81 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00694 AC: 472 AN: 68030

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00713 Hom.: 5

Bravo AF: 0.00526

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00705

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	2	Amyotrophic lateral sclerosis type 4 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)
-	-	2	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.36
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs151237267; hg19: chr9-135202230; COSMIC: COSV99808531;