rs61548169

Variant names:

• chr13-23339758-G-A
• rs61548169
• NM_014363.6:c.4118C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-23339758-G-A
• chr13-23339758-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_014363.6(SACS):​c.4118C>T​(p.Ala1373Val) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,106 control chromosomes in the GnomAD database, including 19 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1373P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (7 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.84
• Publications: 3 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: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-23339758-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1343990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038004518).
• BP6: Variant 13-23339758-G-A is Benign according to our data. Variant chr13-23339758-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235380.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00641 (976/152320) while in subpopulation AFR AF = 0.0224 (930/41576). AF 95% confidence interval is 0.0212. There are 12 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.4118C>T	p.Ala1373Val	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.4145C>T	p.Ala1382Val	missense	Exon 11 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.3677C>T	p.Ala1226Val	missense	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.4118C>T	p.Ala1373Val	missense	Exon 10 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.2431+1687C>T		intron	N/A	ENSP00000406565.2
	SACS	ENST00000682944.1		c.4145C>T	p.Ala1382Val	missense	Exon 11 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 976 AN: 152202 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00170 AC: 426 AN: 251238 AF XY: 0.00121

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000610 AC: 891 AN: 1461786 Hom.: 7 Cov.: 36 AF XY: 0.000498 AC XY: 362 AN XY: 727190

African (AFR) AF: 0.0223 AC: 748 AN: 33478

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111960

Other (OTH) AF: 0.00131 AC: 79 AN: 60390

GnomAD4 genome AF: 0.00641 AC: 976 AN: 152320 Hom.: 12 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74494

African (AFR) AF: 0.0224 AC: 930 AN: 41576

American (AMR) AF: 0.00249 AC: 38 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00276 Hom.: 7

Bravo AF: 0.00772

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.35
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.75	N
PhyloP100		5.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0020	B
Vest4		0.082
MVP		0.68
ClinPred		0.0098	T
GERP RS		4.3
Varity_R		0.049
gMVP		0.29
Mutation Taster		=95/5	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: rs61548169; hg19: chr13-23913897;