rs34382952

Variant names:

• chr13-23330159-T-G
• rs34382952
• NM_014363.6:c.13717A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014363.6(SACS):​c.13717A>C​(p.Asn4573His) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,613,956 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N4573N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (18 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:12
• Conservation: PhyloP100: 6.24
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0107293725).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00326 (496/152340) while in subpopulation AMR AF = 0.00653 (100/15308). AF 95% confidence interval is 0.0055. There are 3 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.13717A>C	p.Asn4573His	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.13744A>C	p.Asn4582His	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.13276A>C	p.Asn4426His	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.13717A>C	p.Asn4573His	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-675A>C		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.13744A>C	p.Asn4582His	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 497 AN: 152222 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00318 AC: 799 AN: 250932 AF XY: 0.00316

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00518

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00453 AC: 6614 AN: 1461616 Hom.: 18 Cov.: 32 AF XY: 0.00442 AC XY: 3217 AN XY: 727114

African (AFR) AF: 0.000627 AC: 21 AN: 33474

American (AMR) AF: 0.00369 AC: 165 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86248

European-Finnish (FIN) AF: 0.00135 AC: 72 AN: 53392

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.00541 AC: 6020 AN: 1111806

Other (OTH) AF: 0.00356 AC: 215 AN: 60388

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152340 Hom.: 3 Cov.: 33 AF XY: 0.00319 AC XY: 238 AN XY: 74496

African (AFR) AF: 0.000770 AC: 32 AN: 41572

American (AMR) AF: 0.00653 AC: 100 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00497 AC: 338 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00454 Hom.: 14

Bravo AF: 0.00358

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00315 AC: 382

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	4	Charlevoix-Saguenay spastic ataxia (7)
-	-	4	not specified (4)
-	1	2	not provided (3)
-	1	1	Hereditary spastic paraplegia (2)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	-0.34	N
PhyloP100		6.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.41
Sift	Benign	0.056	T
Sift4G	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.38
MVP		0.87
ClinPred		0.012	T
GERP RS		5.8
Varity_R		0.72
gMVP		0.49
Mutation Taster		=85/15	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: rs34382952; hg19: chr13-23904298;