rs139517699

Positions:

• chr13-23333208-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_014363.6(SACS):​c.10668G>A​(p.Leu3556=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,597,908 control chromosomes in the GnomAD database, including 2 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 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (2 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.27

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-23333208-C-T is Benign according to our data. Variant chr13-23333208-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 501122.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr13-23333208-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6	c.10668G>A	p.Leu3556=	synonymous_variant	10/10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.10668G>A	p.Leu3556=	synonymous_variant	10/10	5	NM_014363.6	ENSP00000371729	P1

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000478

GnomAD3 exomes AF: 0.000137 AC: 32 AN: 232952 Hom.: 0 AF XY: 0.000103 AC XY: 13 AN XY: 126070

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000768 AC: 111 AN: 1445680 Hom.: 2 Cov.: 34 AF XY: 0.0000724 AC XY: 52 AN XY: 717790

Gnomad4 AFR exome AF: 0.00307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74436

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.000733

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2017	- -

Charlevoix-Saguenay spastic ataxia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.72
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs139517699; hg19: chr13-23907347;