rs34559250

Variant names:

• chr13-23339574-T-C
• rs34559250
• NM_014363.6:c.4302A>G
• SACS p.Leu1434Leu

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.4302A>G​(p.Leu1434Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,612,886 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1434L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.00800
• Publications: 2 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: Myriad Women's Health, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 13-23339574-T-C is Benign according to our data. Variant chr13-23339574-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 311544.
• BP7: Synonymous conserved (PhyloP=-0.008 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000348 (53/152384) while in subpopulation SAS AF = 0.00641 (31/4834). AF 95% confidence interval is 0.00464. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.4302A>G	p.Leu1434Leu	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.4329A>G	p.Leu1443Leu	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.3861A>G	p.Leu1287Leu	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.4302A>G	p.Leu1434Leu	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+1871A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.4329A>G	p.Leu1443Leu	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00128 AC: 321 AN: 251076 AF XY: 0.00158

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000660 AC: 964 AN: 1460502 Hom.: 11 Cov.: 36 AF XY: 0.000910 AC XY: 661 AN XY: 726244

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.0000895 AC: 4 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.00817 AC: 704 AN: 86212

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5766

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1110914

Other (OTH) AF: 0.000696 AC: 42 AN: 60326

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.000523 AC XY: 39 AN XY: 74520

African (AFR) AF: 0.0000481 AC: 2 AN: 41600

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

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

South Asian (SAS) AF: 0.00641 AC: 31 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000458 Hom.: 1

Bravo AF: 0.000253

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Charlevoix-Saguenay spastic ataxia (4)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (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	-0.72
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		-0.0080
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34559250;

hg19: chr13-23913713;