chr15-44621893-A-C

Position:

• chr15-44621893-A-C

Variant summary

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

The ENST00000261866.12(SPG11):​c.2486T>G​(p.Val829Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. V829V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 ENST00000261866.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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=0.31478688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.2486T>G	p.Val829Gly	missense_variant	14/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.2486T>G	p.Val829Gly	missense_variant	14/40	1	NM_025137.4	ENSP00000261866

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Mar 07, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.4	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.78	P;.;B;.
Vest4		0.50
MutPred		0.38		Loss of stability (P = 0.0058);Loss of stability (P = 0.0058);Loss of stability (P = 0.0058);Loss of stability (P = 0.0058);
MVP		0.79
MPC		0.25
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.62

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: rs1555455561; hg19: chr15-44914091;