rs147099630

Variant names:

• chr13-23339410-T-C
• rs147099630
• NM_014363.6:c.4466A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014363.6(SACS):​c.4466A>G​(p.Asn1489Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,610,306 control chromosomes in the GnomAD database, including 117 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1489H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0059 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (108 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:17 O:1
• Conservation: PhyloP100: 1.49
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008807957).
• BP6: Variant 13-23339410-T-C is Benign according to our data. Variant chr13-23339410-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00593 (903/152332) while in subpopulation SAS AF = 0.0263 (127/4824). AF 95% confidence interval is 0.0226. There are 9 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4466A>G	p.Asn1489Ser	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.4493A>G	p.Asn1498Ser	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.4025A>G	p.Asn1342Ser	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.4466A>G	p.Asn1489Ser	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+2035A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.4493A>G	p.Asn1498Ser	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 905 AN: 152214 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00940 AC: 2323 AN: 247218 AF XY: 0.0110

Gnomad AFR exome AF: 0.000866

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0435

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00682

Gnomad OTH exome AF: 0.00967

GnomAD4 exome AF: 0.00790 AC: 11511 AN: 1457974 Hom.: 108 Cov.: 36 AF XY: 0.00888 AC XY: 6437 AN XY: 724824

African (AFR) AF: 0.000812 AC: 27 AN: 33246

American (AMR) AF: 0.00279 AC: 123 AN: 44060

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 1119 AN: 25990

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.0291 AC: 2477 AN: 85152

European-Finnish (FIN) AF: 0.00184 AC: 98 AN: 53298

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5734

European-Non Finnish (NFE) AF: 0.00631 AC: 7011 AN: 1110606

Other (OTH) AF: 0.00953 AC: 574 AN: 60232

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152332 Hom.: 9 Cov.: 33 AF XY: 0.00595 AC XY: 443 AN XY: 74490

African (AFR) AF: 0.00103 AC: 43 AN: 41570

American (AMR) AF: 0.00307 AC: 47 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4824

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10632

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00747 AC: 508 AN: 68032

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00761 Hom.: 24

Bravo AF: 0.00538

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00903 AC: 1096

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00806

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
1	-	4	Charlevoix-Saguenay spastic ataxia (6)
-	-	5	not provided (5)
1	-	-	Abnormal brain morphology (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.49	N
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.48
MVP		0.56
ClinPred		0.011	T
GERP RS		2.2
Varity_R		0.022
gMVP		0.18
Mutation Taster		=92/8	disease causing (ClinVar)

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: rs147099630; hg19: chr13-23913549;