rs200573434

chr15-44663632-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_025137.4(SPG11):c.16G>A(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,595,546 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. G6A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 0.341

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047059953).
• BP6: Variant 15-44663632-C-T is Benign according to our data. Variant chr15-44663632-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216771.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5, Benign=2}. Variant chr15-44663632-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152370) while in subpopulation NFE AF= 0.00215 (146/68030). AF 95% confidence interval is 0.00186. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.16G>A	p.Gly6Arg	missense_variant	1/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.16G>A	p.Gly6Arg	missense_variant	1/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152252 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00129 AC: 276 AN: 214166 Hom.: 1 AF XY: 0.00126 AC XY: 150 AN XY: 119160

Gnomad AFR exome AF: 0.000827

Gnomad AMR exome AF: 0.000701

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0000587

Gnomad SAS exome AF: 0.000140

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.00213 AC: 3075 AN: 1443176 Hom.: 4 Cov.: 32 AF XY: 0.00209 AC XY: 1501 AN XY: 717648

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.000687

Gnomad4 ASJ exome AF: 0.0000776

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.000742

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152370 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74514

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.00153

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00131 AC: 11

ExAC AF: 0.00138 AC: 166

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2021	This variant is associated with the following publications: (PMID: 18337587) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SPG11: BP4 -

Hereditary spastic paraplegia 11 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Amyotrophic lateral sclerosis Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Sep 09, 2020

- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Amyotrophic lateral sclerosis type 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 28, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SPG11-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	9.7
Dann	Benign	0.96
DEOGEN2	Benign	0.010	T;.;T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.61	T;T;T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.64	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.22	T;T;T;T;T
Sift4G	Benign	0.074	T;T;T;D;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.17
MutPred		0.32		Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);
MVP		0.67
MPC		0.041
ClinPred		0.0068	T
GERP RS		2.5
Varity_R		0.036
gMVP		0.23

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: rs200573434; hg19: chr15-44955830; COSMIC: COSV55995618; COSMIC: COSV55995618;