chr15-44563209-G-T

Variant names:

• chr15-44563209-G-T
• rs1060501177
• NM_025137.4:c.7244C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025137.4(SPG11):​c.7244C>A​(p.Ala2415Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.33

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]

EIF3J (HGNC:3270): (eukaryotic translation initiation factor 3 subunit J) This gene encodes a core subunit of the eukaryotic initiation factor 3 complex, which participates in the initiation of translation by aiding in the recruitment of protein and mRNA components to the 40S ribosome. There are pseudogenes for this gene on chromosomes 1, 3, and 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.7244C>A	p.Ala2415Glu	missense_variant	Exon 40 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.7244C>A	p.Ala2415Glu	missense_variant	Exon 40 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1

Oct 17, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with glutamic acid at codon 2415 of the SPG11 protein (p.Ala2415Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SPG11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.55		Gain of sheet (P = 0.0036);.;
MVP		0.86
MPC		0.26
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.81

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: rs1060501177; hg19: chr15-44855407;