rs137905181

Variant names:

• chr13-23334314-A-G
• rs137905181
• NM_014363.6:c.9562T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_014363.6(SACS):​c.9562T>C​(p.Phe3188Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,609,818 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 8.87
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21307245).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000302 (46/152286) while in subpopulation AMR AF = 0.00209 (32/15292). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.9562T>C	p.Phe3188Leu	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.9589T>C	p.Phe3197Leu	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.9121T>C	p.Phe3041Leu	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.9562T>C	p.Phe3188Leu	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-4830T>C		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.9589T>C	p.Phe3197Leu	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000283 AC: 70 AN: 247244 AF XY: 0.000209

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.000802

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000196 AC: 286 AN: 1457532 Hom.: 1 Cov.: 37 AF XY: 0.000178 AC XY: 129 AN XY: 724772

African (AFR) AF: 0.0000301 AC: 1 AN: 33212

American (AMR) AF: 0.000630 AC: 28 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.000652 AC: 17 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 85586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000202 AC: 224 AN: 1109616

Other (OTH) AF: 0.000266 AC: 16 AN: 60182

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74470

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00209 AC: 32 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000472

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Charlevoix-Saguenay spastic ataxia (4)
-	2	-	not provided (2)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.1	L
PhyloP100		8.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.95
MutPred		0.54		Gain of catalytic residue at N3190 (P = 0.003)
MVP		0.92
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.72
gMVP		0.79
Mutation Taster		=91/9	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: rs137905181; hg19: chr13-23908453;