chr15-44622220-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_025137.4(SPG11):c.2444G>A(p.Arg815Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R815M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPG11
NM_025137.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.55

Publications

2 publications found

Variant links:

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]

SPG11 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 11
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
amyotrophic lateral sclerosis type 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Charcot-Marie-Tooth disease axonal type 2X
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
juvenile amyotrophic lateral sclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SPG11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-44622220-C-T is Pathogenic according to our data. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44622220-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1805362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.2444G>A	p.Arg815Lys	missense_variant, splice_region_variant	Exon 13 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 link	c.2444G>A	p.Arg815Lys	missense_variant, splice_region_variant	Exon 13 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251084

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460140

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110728

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:2

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 815 of the SPG11 protein (p.Arg815Lys). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 33059505). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1805362). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg815 amino acid residue in SPG11. Other variant(s) that disrupt this residue have been observed in individuals with SPG11-related conditions (PMID: 19105190), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine (exon 13). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region (NCBI, Decipher, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in a patient with ARHSP-TCC, who also was heterozygote for a VUS missense in HYAL1 gene (PMID: 30212743). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

T;.;T;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.3

M;M;.;M

PhyloP100

3.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.55

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.048

D;D;D;D

Sift4G

Benign

0.18

T;T;T;D

Polyphen

0.11

B;.;B;.

Vest4

0.32

MutPred

0.38

Gain of methylation at R815 (P = 0.0132);Gain of methylation at R815 (P = 0.0132);Gain of methylation at R815 (P = 0.0132);Gain of methylation at R815 (P = 0.0132);

MVP

0.73

MPC

0.13

ClinPred

0.78

GERP RS

5.3

Varity_R

0.18

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.88

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over