rs80338868
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_025137.4(SPG11):c.808G>A(p.Val270Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,614,162 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0080 ( 6 hom., cov: 32)
Exomes 𝑓: 0.0082 ( 62 hom. )
Consequence
SPG11
NM_025137.4 missense
NM_025137.4 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 1.12
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0037087202).
BP6
Variant 15-44657156-C-T is Benign according to our data. Variant chr15-44657156-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 41366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44657156-C-T is described in Lovd as [Likely_benign]. Variant chr15-44657156-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00804 (1224/152296) while in subpopulation NFE AF= 0.00941 (640/68028). AF 95% confidence interval is 0.0088. There are 6 homozygotes in gnomad4. There are 549 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.808G>A | p.Val270Ile | missense_variant | 4/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.808G>A | p.Val270Ile | missense_variant | 4/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes AF: 0.00805 AC: 1225AN: 152178Hom.: 6 Cov.: 32
GnomAD3 genomes
AF:
AC:
1225
AN:
152178
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00608 AC: 1528AN: 251422Hom.: 5 AF XY: 0.00592 AC XY: 805AN XY: 135886
GnomAD3 exomes
AF:
AC:
1528
AN:
251422
Hom.:
AF XY:
AC XY:
805
AN XY:
135886
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00824 AC: 12041AN: 1461866Hom.: 62 Cov.: 31 AF XY: 0.00803 AC XY: 5836AN XY: 727226
GnomAD4 exome
AF:
AC:
12041
AN:
1461866
Hom.:
Cov.:
31
AF XY:
AC XY:
5836
AN XY:
727226
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00804 AC: 1224AN: 152296Hom.: 6 Cov.: 32 AF XY: 0.00737 AC XY: 549AN XY: 74476
GnomAD4 genome
AF:
AC:
1224
AN:
152296
Hom.:
Cov.:
32
AF XY:
AC XY:
549
AN XY:
74476
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
34
ALSPAC
AF:
AC:
43
ESP6500AA
AF:
AC:
43
ESP6500EA
AF:
AC:
89
ExAC
AF:
AC:
737
Asia WGS
AF:
AC:
12
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Benign:6
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Sep 06, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 16, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 15, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 25, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2022 | Variant summary: SPG11 c.808G>A (p.Val270Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0062 in 282816 control chromosomes (gnomAD), including 6 homozygotes. The variant occurs predominantly at a frequency of 0.009 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.808G>A has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia, however it was considered likely to be a polymorphism as it was found at a slightly higher frequency in healthy controls (Stevanin_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SPG11: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2019 | This variant is associated with the following publications: (PMID: 18079167, 25588603, 20301389) - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 23, 2019 | 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. - |
Hereditary spastic paraplegia Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 19, 2021 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Benign
D;D;D;D;D
Sift4G
Benign
T;T;T;D;D
Polyphen
P;.;D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at