13-23333770-A-G

Variant names:

• chr13-23333770-A-G
• rs17078605
• NM_014363.6:c.10106T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014363.6(SACS):​c.10106T>C​(p.Val3369Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,613,526 control chromosomes in the GnomAD database, including 58,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3369G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4559 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53465 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 9.32
• Publications: 35 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), G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023599565).
• BP6: Variant 13-23333770-A-G is Benign according to our data. Variant chr13-23333770-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

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.10106T>C	p.Val3369Ala	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.10133T>C	p.Val3378Ala	missense	Exon 11 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.9665T>C	p.Val3222Ala	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.10106T>C	p.Val3369Ala	missense	Exon 10 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.2432-4286T>C		intron	N/A	ENSP00000406565.2
	SACS	ENST00000682944.1		c.10133T>C	p.Val3378Ala	missense	Exon 11 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34366 AN: 151978 Hom.: 4556 Cov.: 32

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.287 AC: 71875 AN: 250816 AF XY: 0.288

Gnomad AFR exome AF: 0.0881

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.266 AC: 388655 AN: 1461430 Hom.: 53465 Cov.: 61 AF XY: 0.268 AC XY: 195126 AN XY: 727006

African (AFR) AF: 0.0853 AC: 2853 AN: 33466

American (AMR) AF: 0.378 AC: 16886 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10493 AN: 26116

East Asian (EAS) AF: 0.345 AC: 13700 AN: 39688

South Asian (SAS) AF: 0.340 AC: 29363 AN: 86242

European-Finnish (FIN) AF: 0.239 AC: 12762 AN: 53382

Middle Eastern (MID) AF: 0.326 AC: 1879 AN: 5768

European-Non Finnish (NFE) AF: 0.256 AC: 284963 AN: 1111696

Other (OTH) AF: 0.261 AC: 15756 AN: 60380

GnomAD4 genome AF: 0.226 AC: 34381 AN: 152096 Hom.: 4559 Cov.: 32 AF XY: 0.231 AC XY: 17200 AN XY: 74342

African (AFR) AF: 0.0909 AC: 3774 AN: 41522

American (AMR) AF: 0.326 AC: 4972 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1389 AN: 3464

East Asian (EAS) AF: 0.340 AC: 1758 AN: 5176

South Asian (SAS) AF: 0.354 AC: 1707 AN: 4818

European-Finnish (FIN) AF: 0.236 AC: 2493 AN: 10568

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17509 AN: 67976

Other (OTH) AF: 0.257 AC: 540 AN: 2102

Alfa AF: 0.254 Hom.: 14881

Bravo AF: 0.229

TwinsUK AF: 0.251 AC: 932

ALSPAC AF: 0.252 AC: 972

ESP6500AA AF: 0.0962 AC: 424

ESP6500EA AF: 0.260 AC: 2236

ExAC AF: 0.278 AC: 33688

Asia WGS AF: 0.317 AC: 1102 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.268

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Charlevoix-Saguenay spastic ataxia (3)
-	-	3	not provided (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.74	P
Vest4		0.26
ClinPred		0.036	T
GERP RS		5.9
Varity_R		0.13
gMVP		0.53
Mutation Taster		=94/6	polymorphism (auto)

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: rs17078605; hg19: chr13-23907909; COSMIC: COSV66542250;