15-44606073-G-C

Variant names:

• chr15-44606073-G-C
• rs750011115
• NM_025137.4:c.3472C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025137.4(SPG11):​c.3472C>G​(p.Pro1158Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1158P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3685343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.3472C>G	p.Pro1158Ala	missense_variant	Exon 20 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.3472C>G	p.Pro1158Ala	missense_variant	Exon 20 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1

Aug 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with alanine at codon 1158 of the SPG11 protein (p.Pro1158Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.12
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.83
DEOGEN2	Benign	0.086	T;.;T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Uncertain	2.7	M;M;.;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N;N;N;N;D
REVEL	Uncertain	0.43
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Uncertain	0.032	D;D;D;D;T
Polyphen		0.54	P;.;P;.;.
Vest4		0.65
MVP		0.79
MPC		0.24
ClinPred		0.74	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs750011115; hg19: chr15-44898271;