NM_014363.6:c.10611A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_014363.6(SACS):c.10611A>G(p.Ala3537Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,602,018 control chromosomes in the GnomAD database, including 5 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 0.0022 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 1 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:7

Conservation

PhyloP100: 0.0790

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 13-23333265-T-C is Benign according to our data. Variant chr13-23333265-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240890.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Likely_pathogenic=1, Benign=2, Uncertain_significance=1}. Variant chr13-23333265-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.079 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0022 (335/152328) while in subpopulation AFR AF= 0.00661 (275/41586). AF 95% confidence interval is 0.00597. There are 4 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.10611A>G	p.Ala3537Ala	synonymous_variant	Exon 10 of 10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.10611A>G	p.Ala3537Ala	synonymous_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

334

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00661

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.000456

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000823

AC:

197

AN:

239498

Hom.:

AF XY:

0.000673

AC XY:

AN XY:

129310

show subpopulations

Gnomad AFR exome

AF:

0.00677

Gnomad AMR exome

AF:

0.00109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000728

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000447

Gnomad OTH exome

AF:

0.000692

GnomAD4 exome

AF:

0.000479

AC:

694

AN:

1449690

Hom.:

Cov.:

AF XY:

0.000454

AC XY:

327

AN XY:

720152

show subpopulations

Gnomad4 AFR exome

AF:

0.00590

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000117

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000361

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000333

Gnomad4 OTH exome

AF:

0.000903

GnomAD4 genome

AF:

0.00220

AC:

335

AN:

152328

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00661

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00251

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Pathogenic:1Uncertain:1Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SACS: BP4, BP7, BS2 -

Jan 03, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Apr 20, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia

Benign:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Oct 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.7

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over