13-23340449-G-T

Variant names:

• chr13-23340449-G-T
• rs144267558
• NM_014363.6:c.3427C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014363.6(SACS):​c.3427C>A​(p.Gln1143Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00102 in 1,613,992 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. Q1143H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 7.13
• Publications: 11 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), G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009171039).
• BP6: Variant 13-23340449-G-T is Benign according to our data. Variant chr13-23340449-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212112.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00086 (131/152312) while in subpopulation AMR AF = 0.0015 (23/15304). AF 95% confidence interval is 0.00103. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.3427C>A	p.Gln1143Lys	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.3454C>A	p.Gln1152Lys	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.2986C>A	p.Gln996Lys	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.3427C>A	p.Gln1143Lys	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+996C>A		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.3454C>A	p.Gln1152Lys	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00110 AC: 277 AN: 251066 AF XY: 0.00105

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00103 AC: 1512 AN: 1461680 Hom.: 2 Cov.: 36 AF XY: 0.00101 AC XY: 734 AN XY: 727138

African (AFR) AF: 0.000478 AC: 16 AN: 33462

American (AMR) AF: 0.00193 AC: 86 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 107 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86218

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000998 AC: 1110 AN: 1111952

Other (OTH) AF: 0.00152 AC: 92 AN: 60384

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74480

African (AFR) AF: 0.000385 AC: 16 AN: 41568

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68028

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000956 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00106 AC: 129

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.15
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.82	L
PhyloP100		7.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.075
MVP		0.75
ClinPred		0.035	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.32
Mutation Taster		=3/97	disease causing

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: rs144267558; hg19: chr13-23914588;