rs1060501175

chr15-44648965-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025137.4(SPG11):c.1503T>G(p.Phe501Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,768 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.837

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17861897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.1503T>G	p.Phe501Leu	missense_variant	7/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.1503T>G	p.Phe501Leu	missense_variant	7/40	1	NM_025137.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251322 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135820

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727202

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 12, 2016

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. This sequence change replaces phenylalanine with leucine at codon 501 of the SPG11 protein (p.Phe501Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. 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: "Tolerated"; 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	0.90
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.027	T;.;T;.;.
Eigen	Benign	-0.060
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M;M;.;M;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.78	N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.60	T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;D;D
Polyphen		0.22	B;.;B;.;.
Vest4		0.45
MutPred		0.38		Gain of disorder (P = 0.5347);Gain of disorder (P = 0.5347);Gain of disorder (P = 0.5347);Gain of disorder (P = 0.5347);Gain of disorder (P = 0.5347);
MVP		0.64
MPC		0.26
ClinPred		0.49	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.52

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: rs1060501175; hg19: chr15-44941163;