rs150218102

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025137.4(SPG11):c.4923G>C(p.Lys1641Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,613,906 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K1641K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0042 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00038 ( 7 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.933

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01241833).

BP6

Variant 15-44585834-C-G is Benign according to our data. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44585834-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 376990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00419 (637/152130) while in subpopulation AFR AF = 0.0149 (616/41470). AF 95% confidence interval is 0.0139. There are 4 homozygotes in GnomAd4. There are 283 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.4923G>C	p.Lys1641Asn	missense_variant	Exon 29 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.4923G>C	p.Lys1641Asn	missense_variant	Exon 29 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00420

AC:

639

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00103

AC:

259

AN:

251238

AF XY:

0.000670

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000376

AC:

550

AN:

1461776

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

209

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0140

AC:

467

AN:

33476

American (AMR)

AF:

0.000537

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111952

Other (OTH)

AF:

0.000729

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00419

AC:

637

AN:

152130

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

283

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0149

AC:

616

AN:

41470

American (AMR)

AF:

0.000982

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.00444

ESP6500AA

AF:

0.0130

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00122

AC:

148

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Aug 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25588603) -

Nov 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 11

Benign:2

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 21, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 5

Benign:1

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X

Benign:1

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

-0.065

MutationAssessor

Uncertain

2.8

M;M;.;M

PhyloP100

0.93

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.95

N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.034

D;T;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.67

MutPred

0.45

Loss of methylation at K1641 (P = 0.0163);Loss of methylation at K1641 (P = 0.0163);Loss of methylation at K1641 (P = 0.0163);Loss of methylation at K1641 (P = 0.0163);

MVP

0.76

MPC

0.28

ClinPred

0.026

GERP RS

3.6

Varity_R

0.089

gMVP

0.55

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over