rs111540787

Variant names:

• chr13-23335537-A-C
• rs111540787
• NM_014363.6:c.8339T>G
• SACS p.Phe2780Cys

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The NM_014363.6(SACS):​c.8339T>G​(p.Phe2780Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,613,692 control chromosomes in the GnomAD database, including 22 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 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (21 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7
• Conservation: PhyloP100: 8.87
• Publications: 13 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: Myriad Women's Health, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.077881575).
• BP6: Variant 13-23335537-A-C is Benign according to our data. Variant chr13-23335537-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240902.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0033 (502/152208) while in subpopulation NFE AF = 0.00525 (357/67980). AF 95% confidence interval is 0.0048. There are 1 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.8339T>G	p.Phe2780Cys	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.8366T>G	p.Phe2789Cys	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.7898T>G	p.Phe2633Cys	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.8339T>G	p.Phe2780Cys	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+5908T>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.8366T>G	p.Phe2789Cys	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152090 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00286 AC: 718 AN: 250866 AF XY: 0.00279

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00387

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00498 AC: 7278 AN: 1461484 Hom.: 21 Cov.: 37 AF XY: 0.00482 AC XY: 3502 AN XY: 727066

African (AFR) AF: 0.000866 AC: 29 AN: 33470

American (AMR) AF: 0.00183 AC: 82 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86250

European-Finnish (FIN) AF: 0.00419 AC: 223 AN: 53172

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00594 AC: 6608 AN: 1111906

Other (OTH) AF: 0.00397 AC: 240 AN: 60390

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152208 Hom.: 1 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74436

African (AFR) AF: 0.000915 AC: 38 AN: 41542

American (AMR) AF: 0.00294 AC: 45 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00525 AC: 357 AN: 67980

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00413 Hom.: 10

Bravo AF: 0.00311

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	3	1	Charlevoix-Saguenay spastic ataxia (4)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	not specified (1)
-	-	1	SACS-related disorder (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.078	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.58
gMVP		0.73
Mutation Taster		=83/17	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs111540787;

hg19: chr13-23909676;

COSMIC: COSV99063608;