rs78183930

Positions:

• chr15-44626492-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.26

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]

ACMG classification

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	UniProt
SPG11	NM_025137.4	c.2083G>A	p.Ala695Thr	missense_variant	11/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.2083G>A	p.Ala695Thr	missense_variant	11/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1883 AN: 152056 Hom.: 25 Cov.: 32

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.: 44 AF XY: 0.0129 AC XY: 1743 AN XY: 135518

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.: 31 AF XY: 0.0133 AC XY: 9681 AN XY: 726970

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.: 25 Cov.: 32 AF XY: 0.0132 AC XY: 985 AN XY: 74384

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.: 42

Bravo AF: 0.00851

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.0131 AC: 113

ExAC AF: 0.0125 AC: 1517

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 15, 2016	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 15, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not specified Benign:4

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SPG11: BS1, BS2 -
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	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
MetaRNN	Benign	0.0085	T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.7	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
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	T
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

Other links and lift over

dbSNP: rs78183930; hg19: chr15-44918690; COSMIC: COSV105072607; COSMIC: COSV105072607;