rs78183930

Positions:

chr15-44626492-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025137.4(SPG11):c.2083G>A(p.Ala695Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0132 in 1,613,566 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 25 hom., cov: 32)

Exomes 𝑓: 0.013 ( 189 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.26

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=0.008483201).

BP6

Variant 15-44626492-C-T is Benign according to our data. Variant chr15-44626492-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44626492-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1883/152174) while in subpopulation NFE AF= 0.0172 (1168/68018). AF 95% confidence interval is 0.0164. There are 25 homozygotes in gnomad4. There are 985 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.2083G>A	p.Ala695Thr	missense_variant	11/40	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.2083G>A	p.Ala695Thr	missense_variant	11/40	1	NM_025137.4	ENSP00000261866		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1883

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.00720

GnomAD3 exomes

AF:

0.0129

AC:

3224

AN:

250704

Hom.:

AF XY:

0.0129

AC XY:

1743

AN XY:

135518

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00342

Gnomad ASJ exome

AF:

0.0120

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00266

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0120

GnomAD4 exome

AF:

0.0133

AC:

19457

AN:

1461392

Hom.:

189

Cov.:

AF XY:

0.0133

AC XY:

9681

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.0119

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00290

Gnomad4 FIN exome

AF:

0.0441

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0124

AC:

1883

AN:

152174

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

985

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0442

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.0137

Hom.:

Bravo

AF:

0.00851

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.0131

AC:

113

ExAC

AF:

0.0125

AC:

1517

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 15, 2014	- -
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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 15, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SPG11: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25174650, 27957547) -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;.;T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;D

MetaRNN

Benign

0.0085

T;T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.7

M;M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.3

N;N;N;N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.78

MPC

0.26

ClinPred

0.020

GERP RS

5.9

Varity_R

0.18

gMVP

0.61

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