rs149638449

Variant names:

• chr13-23354727-C-T
• rs149638449
• NM_014363.6:c.1885G>A

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.1885G>A​(p.Ala629Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00063 in 1,613,524 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. A629V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (2 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 1.29
• Publications: 4 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=0.027523398).
• BP6: Variant 13-23354727-C-T is Benign according to our data. Variant chr13-23354727-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448197.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00067 (102/152346) while in subpopulation AMR AF = 0.00307 (47/15302). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1885G>A	p.Ala629Thr	missense	Exon 8 of 10	NP_055178.3
	SACS	NM_001437336.1		c.1885G>A	p.Ala629Thr	missense	Exon 8 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.1444G>A	p.Ala482Thr	missense	Exon 6 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.1885G>A	p.Ala629Thr	missense	Exon 8 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.1885G>A	p.Ala629Thr	missense	Exon 8 of 11	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.1885G>A	p.Ala629Thr	missense	Exon 8 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000534 AC: 134 AN: 250804 AF XY: 0.000509

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000626 AC: 914 AN: 1461178 Hom.: 2 Cov.: 32 AF XY: 0.000623 AC XY: 453 AN XY: 726788

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000358 AC: 16 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86204

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53346

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.000721 AC: 801 AN: 1111514

Other (OTH) AF: 0.000696 AC: 42 AN: 60368

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74498

African (AFR) AF: 0.000265 AC: 11 AN: 41586

American (AMR) AF: 0.00307 AC: 47 AN: 15302

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

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68032

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

Alfa AF: 0.000675 Hom.: 1

Bravo AF: 0.000699

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Charlevoix-Saguenay spastic ataxia (2)
-	1	1	not provided (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	SACS-related disorder (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.071
Sift	Benign	0.079	T
Sift4G	Uncertain	0.018	D
Polyphen		0.0	B
Vest4		0.042
MVP		0.32
ClinPred		0.012	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.027
gMVP		0.14
Mutation Taster		=298/2	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: rs149638449; hg19: chr13-23928866; COSMIC: COSV66545356;