rs312262745

Variant names:

• chr15-44621771-T-C
• rs312262745
• NM_025137.4:c.2608A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_025137.4(SPG11):​c.2608A>G​(p.Ile870Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 3.31

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-44621771-T-C is Pathogenic according to our data. Variant chr15-44621771-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 41293.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.2608A>G	p.Ile870Val	missense_variant	Exon 14 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.2608A>G	p.Ile870Val	missense_variant	Exon 14 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Pathogenic:1

Oct 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SPG11 c.2608A>G (p.Ile870Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251328 control chromosomes. c.2608A>G has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Hereditary Spastic Paraplegia, Type 11 (Pippucci_2009, Orlacchio_2010, Fu_20221). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35464835, 20110243, 19087158). ClinVar contains an entry for this variant (Variation ID: 41293). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary spastic paraplegia 11 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Benign	0.66
DEOGEN2	Benign	0.011	T;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.065
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.5	M;M;.;M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.10	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.11	B;.;B;.
Vest4		0.34
MutPred		0.13		Loss of catalytic residue at P872 (P = 0.0298);Loss of catalytic residue at P872 (P = 0.0298);Loss of catalytic residue at P872 (P = 0.0298);Loss of catalytic residue at P872 (P = 0.0298);
MVP		0.61
MPC		0.063
ClinPred		0.40	T
GERP RS		4.6
Varity_R		0.033
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1
DS_DL_spliceai		0.61		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs312262745; hg19: chr15-44913969;