rs150218102

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.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 (★★).

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

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 links:

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=0.01241833).

BP6

Variant 15-44585834-C-G is Benign according to our data. Variant chr15-44585834-C-G is described in ClinVar as [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 Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.4923G>C	p.Lys1641Asn	missense_variant	29/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.4923G>C	p.Lys1641Asn	missense_variant	29/40	1	NM_025137.4	ENSP00000261866		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

GnomAD3 exomes

AF:

0.00103

AC:

259

AN:

251238

Hom.:

AF XY:

0.000670

AC XY:

AN XY:

135788

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 SAS 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

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.00419

AC:

637

AN:

152130

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

283

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0149

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00190

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2019	This variant is associated with the following publications: (PMID: 25588603) -

Hereditary spastic paraplegia 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 21, 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

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

MutationTaster

Benign

1.0

D;D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over