rs3759874

Variant names:

• chr15-44651600-G-A
• rs3759874
• NM_025137.4:c.1347C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025137.4(SPG11):​c.1347C>T​(p.Thr449Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,178 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 32)
  • Exomes 𝑓: 0.010 (298 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.287

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-44651600-G-A is Benign according to our data. Variant chr15-44651600-G-A is described in ClinVar as [Benign]. Clinvar id is 130363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44651600-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.287 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.1347C>T	p.Thr449Thr	synonymous_variant	Exon 6 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.1347C>T	p.Thr449Thr	synonymous_variant	Exon 6 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2199 AN: 152186 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0963

Gnomad SAS AF: 0.0484

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.0184 AC: 4635 AN: 251470 Hom.: 130 AF XY: 0.0185 AC XY: 2520 AN XY: 135912

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0947

Gnomad SAS exome AF: 0.0367

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0102 AC: 14867 AN: 1461874 Hom.: 298 Cov.: 35 AF XY: 0.0109 AC XY: 7910 AN XY: 727238

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.0738

Gnomad4 SAS exome AF: 0.0364

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.00489

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0145 AC: 2214 AN: 152304 Hom.: 57 Cov.: 32 AF XY: 0.0174 AC XY: 1298 AN XY: 74480

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0966

Gnomad4 SAS AF: 0.0483

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00629 Hom.: 3

Bravo AF: 0.0128

Asia WGS AF: 0.0750 AC: 261 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 11 Benign:3

May 15, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary spastic paraplegia Benign:1

Dec 14, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Amyotrophic lateral sclerosis type 5 Benign:1

-

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.6
DANN	Benign	0.27

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: rs3759874; hg19: chr15-44943798; COSMIC: COSV55998769;