rs200220848

chr15-44573742-A-Cchr15-44573742-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_025137.4(SPG11):c.6010T>G(p.Leu2004Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L2004S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: -0.00900

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025183946).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000279 (408/1461876) while in subpopulation AMR AF= 0.00215 (96/44720). AF 95% confidence interval is 0.0018. There are 0 homozygotes in gnomad4_exome. There are 194 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.6010T>G	p.Leu2004Val	missense_variant	32/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.6010T>G	p.Leu2004Val	missense_variant	32/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152102 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 251048 Hom.: 0 AF XY: 0.000391 AC XY: 53 AN XY: 135710

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00214

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: 0.000194

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000267 AC XY: 194 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152102 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74300

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000299 Hom.: 1

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 19, 2023	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2016	The L2004V variant in the SPG11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L2004V variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L2004V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, in silico splice prediction models indicate that the c.6010 T>G substitution (aka L2004V) could potentially create a new cryptic splice donor site in exon 32 which may supplant the natural donor site and lead to abnormal splicing. However, in the absence of RNA/functional studies, the actual effect of c.6010 T>G in this individual is unknown. We interpret L2004V as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2023	Variant summary: SPG11 c.6010T>G (p.Leu2004Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251048 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.00047 vs 0.0011), allowing no conclusion about variant significance. c.6010T>G has been reported in the literature in at least one individual affected with Amyotrophic Lateral Sclerosis (ALS) with unspecified genotype (e.g. Grassano_2022) and in at least one unaffected control individual in an ALS study (e.g. Couthouis_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia, Type 11. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35896380, 32987860, 25299611). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia 11 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Uncertain significance, 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, 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The p.L2004V variant (also known as c.6010T>G), located in coding exon 32 of the SPG11 gene, results from a T to G substitution at nucleotide position 6010. The leucine at codon 2004 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Pathogenic	0.30
Cadd	Benign	7.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	2.9	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.18	B;B;.
Vest4		0.83
MVP		0.62
MPC		0.21
ClinPred		0.16	T
GERP RS		-2.2
Varity_R		0.43
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200220848; hg19: chr15-44865940;