Variant 15-44657229-CAT-C details in Genebe, Genetics Data Aggregator

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 15-44657229-CAT-C is Pathogenic according to our data. Variant chr15-44657229-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44657229-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.733_734del	p.Met245ValfsTer2	frameshift_variant	4/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.733_734del	p.Met245ValfsTer2	frameshift_variant	4/40	1	NM_025137.4		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

7

AN:

152200

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

17

AN:

251452

Hom.:

0

AF XY:

0.0000662

AC XY:

9

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000711

AC:

104

AN:

1461870

Hom.:

0

AF XY:

0.0000646

AC XY:

47

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000737

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000460

AC:

7

AN:

152200

Hom.:

0

Cov.:

32

AF XY:

0.0000672

AC XY:

5

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

0

Bravo

AF:

0.0000642

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:9Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 01, 2018	The observed variant c.733_734delAT (p.M245Vfs) is not reported in The 1000 Genomes database and its minor allele frequency in ExAC database is 0.0001071. The in silico prediction for the variant is pathogenic by MutationTaster2. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change creates a premature translational stop signal (p.Met245Valfs*2) 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 (rs312262720, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC and juvenile amyotrophic lateral sclerosis (PMID: 17322883, 17717710, 18067136, 18079167, 18332254, 18835492, 19105190, 19438933, 20110243, 22175763, 22237444, 22696581, 24833714, 27071356). ClinVar contains an entry for this variant (Variation ID: 1112). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Met245ValfsTer2 variant in SPG11 was identified by our study in the compound heterozygous state, along with another pathogenic variant, in two siblings with spastic paraplegia. The presence of this variant in combination with a reported pathogenic variant and in an individual with spastic paraplegia increases the likelihood that the p.Met245ValfsTer2 variant is pathogenic. The p.Met245ValfsTer2 variant in SPG11 has been well-reported in the literature. This variant has been reported in greater than 22 individuals from Italy, Japan, France, Tunisia, Sicily, Korea, Spain, China, and Portugal with spastic paraplegia in the homozygous and compound heterozygous state, segregated with disease in 12 affected relatives from 5 families (PMID: 17717710, 20110243, 17322883, 18079167, 22175763, 18332254, 24833714, 22696581, 22237444, 18067136, 18835492), but has been identified in 0.006133% (17/277208) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs312262720). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1112). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 245 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive spastic paraplegia. In summary, the p.Met245ValfsTer2variant is pathogenic based off of our findings, multiple reports of pathogenicity in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PVS1, PM3, PP1_Moderate (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift deletion p.M245Vfs2 in SPG11 (NM_025137.4) has been previously reported in many individuals affected with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC (Stevanin et al, 2007;Del Bo et al. 2007). This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 2 residues until a stop codon is reached. The p.M245Vfs2 variant is a loss of function variant in the gene SPG11, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

Hereditary spastic paraplegia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 14, 2022	- -
Pathogenic, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2022	Variant summary: SPG11 c.733_734delAT (p.Met245ValfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are associated with Spastic Paraplegia in HGMD. The variant allele was found at a frequency of 6.8e-05 in 251452 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (6.8e-05 vs 0.0011). c.733_734delAT has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia (examples: Boukhris_2009 and Stevanin_2008). These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

Abnormal central motor function

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2020

The c.733_734delAT (p.M245Vfs*2) alteration, located in coding exon 4 of the SPG11 gene, results from a deletion of 2 nucleotides from position 733 to 734, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the c.733_734delAT alteration was observed in 0.006% (18/282852) of total alleles studied. In multiple individuals with spastic paraplegia with thin corpus callosum, this alteration has been detected in the homozygous state or in conjunction with a second disease-causing allele (Stevanin, 2007; Boukhris, 2008; Pensato, 2014; Dong, 2018; Wei, 2019). This alteration was also identified in a patient meeting diagnostic criteria for amyotrophic lateral sclerosis (ALS) and a brain MRI which was negative for thin corpus callosum and white matter abnormalities; this individual was also heterozygous for a nonsense variant in SPG11 (Orlacchio, 2010). Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 05, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2021

Frameshift 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17717710, 18332254, 20110243, 22175763, 17322883, 18067136, 27071356, 31227335, 31289639, 31969655, 29980238, 31589614) -

Amyotrophic lateral sclerosis type 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 05-07-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

15-44657229-CAT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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