rs36014111

Positions:

• chr15-44608477-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_025137.4(SPG11):​c.3420G>A​(p.Leu1140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,613,804 control chromosomes in the GnomAD database, including 1,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (123 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1823 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.150

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 15-44608477-C-T is Benign according to our data. Variant chr15-44608477-C-T is described in ClinVar as [Benign]. Clinvar id is 41305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44608477-C-T is described in Lovd as [Benign]. Variant chr15-44608477-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.3420G>A	p.Leu1140=	synonymous_variant	19/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.3420G>A	p.Leu1140=	synonymous_variant	19/40	1	NM_025137.4	ENSP00000261866

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4943 AN: 152082 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0302

GnomAD3 exomes AF: 0.0356 AC: 8938 AN: 251396 Hom.: 224 AF XY: 0.0352 AC XY: 4778 AN XY: 135864

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.0726

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0540

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0457 AC: 66724 AN: 1461604 Hom.: 1823 Cov.: 31 AF XY: 0.0445 AC XY: 32327 AN XY: 727100

Gnomad4 AFR exome AF: 0.00702

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.0728

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00480

Gnomad4 FIN exome AF: 0.0363

Gnomad4 NFE exome AF: 0.0528

Gnomad4 OTH exome AF: 0.0398

GnomAD4 genome AF: 0.0325 AC: 4943 AN: 152200 Hom.: 123 Cov.: 32 AF XY: 0.0305 AC XY: 2268 AN XY: 74404

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.0291

Gnomad4 ASJ AF: 0.0757

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0317

Gnomad4 NFE AF: 0.0494

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.0454 Hom.: 120

Bravo AF: 0.0313

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0446

EpiControl AF: 0.0470

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 15, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Amyotrophic lateral sclerosis type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Charcot-Marie-Tooth disease axonal type 2X Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	7.1
DANN	Benign	0.76

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: rs36014111; hg19: chr15-44900675;