rs376828731

Positions:

• chr15-44657227-C-T

Variant summary

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

The NM_025137.4(SPG11):​c.737G>A​(p.Cys246Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.374

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=0.09523663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.737G>A	p.Cys246Tyr	missense_variant	4/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.737G>A	p.Cys246Tyr	missense_variant	4/40	1	NM_025137.4	ENSP00000261866

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251450 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727234

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 246 of the SPG11 protein (p.Cys246Tyr). This variant is present in population databases (rs376828731, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 316112). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPG11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

Amyotrophic lateral sclerosis type 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Charcot-Marie-Tooth disease axonal type 2X Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.50
DANN	Benign	0.55
DEOGEN2	Benign	0.028	T;.;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.63	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.17	N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.096
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Uncertain	0.037	D;D;D;D;D
Polyphen		0.0	B;.;B;.;.
Vest4		0.24
MVP		0.58
MPC		0.094
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.041
gMVP		0.28

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: rs376828731; hg19: chr15-44949425;