Variant rs312262737 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025137.4(SPG11):c.2146C>T(p.Gln716*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SPG11
NM_025137.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:2O:1

Conservation

PhyloP100: 3.46

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:

SPG11 (HGNC:):

SPG11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-44626429-G-A is Pathogenic according to our data. Variant chr15-44626429-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44626429-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.2146C>T	p.Gln716*	stop_gained	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.2146C>T	p.Gln716*	stop_gained	11/40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251152

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000133

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:4Uncertain:1Other:1

Pathogenic, no assertion criteria provided	research	Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology	Jan 02, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SPG11 c.2146C>T (p.Gln716Ter) variant is a stop gained variant that is predicted to result in prematire termination of the protein. The p.Gln716Ter variant has been reported in two studies in which it is found in a total of four patients with spastic paraplegia including in three in a homozygous state (including two siblings) and in one in a compound heterozygous state (Southgate et al. 2010; Kara et al. 2016). The p.Gln716Ter variant was also detected in a heterozygous state in the unaffected parents of the homozygous siblings (Southgate et al. 2010). The p.Gln716Ter variant was absent from 180 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on one allele only but in an area of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and evidence from the literature, the p. Gln716Ter variant is classified as likely pathogenic for the autosomal recessive form of spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed stop gained variant c.2146C>T(p.Gln716Ter) in SPG11 gene has been reported previously in homozygous state in multiple individuals with hereditary spastic paraplegia (Manole A, et al., 2016, Kara E, et al., 2016, Southgate L, et al., 2010). The c.2146C>T variant has 0.0004% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance/Likely Pathogenic/Pathogenic.This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Southgate L, et al., 2010). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Gln716*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs312262737, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 20390432, 27217339, 27544499). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41285). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, flagged submission	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 03, 2015	The observed variant c.2146C>T (p.Gln716Ter) is not reported in 1000 Genomes and its minor allele frequency ExAC databases is 0.000008252. The in silico prediction of the variant is disease causing by MutationTaster2. -

Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000041285, PMID:20390432). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, flagged submission	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 01, 2022	A heterozygous nonsense variation in exon 11 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 716 (p.Gln716Ter) was detected. The observed variation has previously been reported in patients affected with hereditary spastic paraplegia . The p.Gln716Ter variant has not been reported in the 1000 genomes and gnomAD database. The reference codon is conserved across species. In summary, the varint meets the criteria to be classified as variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed variant c.2146C>T (p.Gln716Ter) in SPG11 gene has been reported in homozygous and compound heterozygous state in individuals affected with SPG11 related disorder (Manole A et al. 2016). The p.Gln716Ter variant has allele frequency 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain significance / Likely pathogenic / Pathogenic. The nucleotide change c.2146C>T in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27544499, 20390432, 30212743, 31069529, 27217339) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.92

Vest4

0.95

GERP RS

5.8

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