rs762177930

Variant names:

• chr15-44629344-T-C
• rs762177930
• NM_025137.4:c.1780A>G

Variant summary

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

The NM_025137.4(SPG11):​c.1780A>G​(p.Ile594Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000027 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.70

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=0.1716147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.1780A>G	p.Ile594Val	missense_variant	Exon 9 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.1780A>G	p.Ile594Val	missense_variant	Exon 9 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251364 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135876

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727222

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1780A>G (p.I594V) alteration is located in exon 9 (coding exon 9) of the SPG11 gene. This alteration results from a A to G substitution at nucleotide position 1780, causing the isoleucine (I) at amino acid position 594 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 11 Uncertain:1

Mar 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 594 of the SPG11 protein (p.Ile594Val). This variant is present in population databases (rs762177930, gnomAD 0.002%). 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: 582658). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;.;T;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.0098
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M;M;.;M;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.24	N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.064	T;T;T;T;T
Polyphen		0.78	P;.;P;.;.
Vest4		0.35
MutPred		0.17		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.61
MPC		0.037
ClinPred		0.18	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.16

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: rs762177930; hg19: chr15-44921542;