rs79708848

chr15-44633542-A-Cchr15-44633542-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025137.4(SPG11):c.1698T>G(p.Asp566Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,609,150 control chromosomes in the GnomAD database, including 286 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. D566N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 31)
  • Exomes 𝑓: 0.017 (265 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -0.131

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004883647).
• BP6: Variant 15-44633542-A-C is Benign according to our data. Variant chr15-44633542-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219609.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=2}. Variant chr15-44633542-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1810/152096) while in subpopulation NFE AF= 0.0199 (1355/67968). AF 95% confidence interval is 0.0191. There are 21 homozygotes in gnomad4. There are 830 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.1698T>G	p.Asp566Glu	missense_variant	8/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.1698T>G	p.Asp566Glu	missense_variant	8/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1811 AN: 151980 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00702

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0110 AC: 2749 AN: 250768 Hom.: 23 AF XY: 0.0107 AC XY: 1457 AN XY: 135544

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000985

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0166 AC: 24242 AN: 1457054 Hom.: 265 Cov.: 30 AF XY: 0.0161 AC XY: 11658 AN XY: 725196

Gnomad4 AFR exome AF: 0.00231

Gnomad4 AMR exome AF: 0.00573

Gnomad4 ASJ exome AF: 0.00445

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0119 AC: 1810 AN: 152096 Hom.: 21 Cov.: 31 AF XY: 0.0112 AC XY: 830 AN XY: 74372

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00701

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0163 Hom.: 39

Bravo AF: 0.0107

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0184 AC: 158

ExAC AF: 0.0111 AC: 1349

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0151

EpiControl AF: 0.0174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary spastic paraplegia 11 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Dec 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, 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 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	- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	3.4
Dann	Benign	0.96
DEOGEN2	Benign	0.011	T;.;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.72	T;T;T;T;T
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M;M;.;M;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.45	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.58	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.67	P;.;B;.;.
Vest4		0.20
MutPred		0.12		Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MPC		0.036
ClinPred		0.021	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.12

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: rs79708848; hg19: chr15-44925740; COSMIC: COSV55990757;