rs75430389

chr15-44592387-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025137.4(SPG11):c.4687A>G(p.Arg1563Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000954 in 1,612,610 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.81

Genes affected

SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005633235).
• BP6: Variant 15-44592387-T-C is Benign according to our data. Variant chr15-44592387-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 188084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44592387-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00493 (751/152292) while in subpopulation AFR AF= 0.0172 (717/41570). AF 95% confidence interval is 0.0162. There are 10 homozygotes in gnomad4. There are 353 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.4687A>G	p.Arg1563Gly	missense_variant	27/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.4687A>G	p.Arg1563Gly	missense_variant	27/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 752 AN: 152174 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00131 AC: 330 AN: 251284 Hom.: 3 AF XY: 0.000935 AC XY: 127 AN XY: 135832

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000539 AC: 787 AN: 1460318 Hom.: 8 Cov.: 29 AF XY: 0.000486 AC XY: 353 AN XY: 726572

Gnomad4 AFR exome AF: 0.0196

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.000978

GnomAD4 genome AF: 0.00493 AC: 751 AN: 152292 Hom.: 10 Cov.: 31 AF XY: 0.00474 AC XY: 353 AN XY: 74474

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.000908 Hom.: 1

Bravo AF: 0.00594

ESP6500AA AF: 0.0162 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Amyotrophic lateral sclerosis type 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Charcot-Marie-Tooth disease axonal type 2X Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.;T;.
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N;N;.;N
MutationTaster	Benign	0.54	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.26	N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.025	D;T;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.024	B;.;B;.
Vest4		0.34
MVP		0.62
MPC		0.043
ClinPred		0.017	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.26

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: rs75430389; hg19: chr15-44884585;