rs148878361

Variant names:

• chr13-23340747-T-C
• rs148878361
• NM_014363.6:c.3129A>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.3129A>G​(p.Ser1043Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,604,468 control chromosomes in the GnomAD database, including 28 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 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (25 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.0930
• Publications: 1 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=-0.86).
• BP6: Variant 13-23340747-T-C is Benign according to our data. Variant chr13-23340747-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240898.
• BP7: Synonymous conserved (PhyloP=-0.093 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00283 (431/152346) while in subpopulation NFE AF = 0.00523 (356/68024). AF 95% confidence interval is 0.00478. There are 3 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.3129A>G	p.Ser1043Ser	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.3156A>G	p.Ser1052Ser	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.2688A>G	p.Ser896Ser	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.3129A>G	p.Ser1043Ser	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+698A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.3156A>G	p.Ser1052Ser	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152228 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00307 AC: 746 AN: 243084 AF XY: 0.00325

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000720

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00519 AC: 7535 AN: 1452122 Hom.: 25 Cov.: 36 AF XY: 0.00505 AC XY: 3648 AN XY: 721754

African (AFR) AF: 0.000637 AC: 21 AN: 32986

American (AMR) AF: 0.00134 AC: 58 AN: 43238

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25568

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00137 AC: 116 AN: 84418

European-Finnish (FIN) AF: 0.00103 AC: 54 AN: 52476

Middle Eastern (MID) AF: 0.000701 AC: 4 AN: 5704

European-Non Finnish (NFE) AF: 0.00627 AC: 6943 AN: 1108196

Other (OTH) AF: 0.00559 AC: 335 AN: 59918

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152346 Hom.: 3 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74502

African (AFR) AF: 0.000794 AC: 33 AN: 41576

American (AMR) AF: 0.00163 AC: 25 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00523 AC: 356 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00380 Hom.: 1

Bravo AF: 0.00300

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Charlevoix-Saguenay spastic ataxia (5)
-	-	4	not provided (4)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not specified (1)
-	-	1	SACS-related disorder (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.57
PhyloP100		-0.093
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: rs148878361; hg19: chr13-23914886;