rs35799469

Variant names:

• chr13-23331227-T-C
• rs35799469
• NM_014363.6:c.12649A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014363.6(SACS):​c.12649A>G​(p.Asn4217Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,886 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N4217K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (12 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.45
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038977861).
• BP6: Variant 13-23331227-T-C is Benign according to our data. Variant chr13-23331227-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235607.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00735 (1119/152332) while in subpopulation AFR AF = 0.0253 (1052/41572). AF 95% confidence interval is 0.024. There are 12 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.12649A>G	p.Asn4217Asp	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.12676A>G	p.Asn4226Asp	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.12208A>G	p.Asn4070Asp	missense	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.12649A>G	p.Asn4217Asp	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-1743A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.12676A>G	p.Asn4226Asp	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152214 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

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: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00196 AC: 492 AN: 250752 AF XY: 0.00144

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000753 AC: 1101 AN: 1461554 Hom.: 12 Cov.: 33 AF XY: 0.000670 AC XY: 487 AN XY: 727074

African (AFR) AF: 0.0265 AC: 885 AN: 33438

American (AMR) AF: 0.00141 AC: 63 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111840

Other (OTH) AF: 0.00176 AC: 106 AN: 60386

GnomAD4 genome AF: 0.00735 AC: 1119 AN: 152332 Hom.: 12 Cov.: 32 AF XY: 0.00711 AC XY: 530 AN XY: 74498

African (AFR) AF: 0.0253 AC: 1052 AN: 41572

American (AMR) AF: 0.00353 AC: 54 AN: 15298

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: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00322 Hom.: 11

Bravo AF: 0.00793

ESP6500AA AF: 0.0227 AC: 100

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Charlevoix-Saguenay spastic ataxia (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.5
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.28
Sift	Benign	0.78	T
Sift4G	Benign	0.14	T
Polyphen		0.022	B
Vest4		0.13
MVP		0.75
ClinPred		0.0081	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.32
Mutation Taster		=98/2	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: rs35799469; hg19: chr13-23905366;