rs137856939

Variant names:

• chr13-23333265-T-C
• rs137856939
• NM_014363.6:c.10611A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014363.6(SACS):​c.10611A>G​(p.Ala3537Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,602,018 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.0022 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7
• Conservation: PhyloP100: 0.0790
• Publications: 0 publications found

Genes affected

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia, G2P, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 13-23333265-T-C is Benign according to our data. Variant chr13-23333265-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240890.
• BP7: Synonymous conserved (PhyloP=0.079 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0022 (335/152328) while in subpopulation AFR AF = 0.00661 (275/41586). AF 95% confidence interval is 0.00597. There are 4 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. 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
	SACS	NM_014363.6	MANE Select	c.10611A>G	p.Ala3537Ala	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.10638A>G	p.Ala3546Ala	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.10170A>G	p.Ala3390Ala	synonymous	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.10611A>G	p.Ala3537Ala	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-3781A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.10638A>G	p.Ala3546Ala	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152210 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00661

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

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: 0.000456

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000823 AC: 197 AN: 239498 AF XY: 0.000673

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.000692

GnomAD4 exome AF: 0.000479 AC: 694 AN: 1449690 Hom.: 1 Cov.: 34 AF XY: 0.000454 AC XY: 327 AN XY: 720152

African (AFR) AF: 0.00590 AC: 193 AN: 32738

American (AMR) AF: 0.00123 AC: 52 AN: 42262

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000361 AC: 3 AN: 83194

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53106

Middle Eastern (MID) AF: 0.00335 AC: 19 AN: 5674

European-Non Finnish (NFE) AF: 0.000333 AC: 369 AN: 1107716

Other (OTH) AF: 0.000903 AC: 54 AN: 59804

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152328 Hom.: 4 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74508

African (AFR) AF: 0.00661 AC: 275 AN: 41586

American (AMR) AF: 0.00183 AC: 28 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00169 Hom.: 2

Bravo AF: 0.00251

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	2	Charlevoix-Saguenay spastic ataxia (4)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		0.079
Mutation Taster		=100/0	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: rs137856939; hg19: chr13-23907404;