15-44565961-T-G

Position:

• chr15-44565961-T-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.6892A>C​(p.Ile2298Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.490

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]

SPG11 (HGNC:):

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=0.20820135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.6892A>C	p.Ile2298Leu	missense_variant	38/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.6892A>C	p.Ile2298Leu	missense_variant	38/40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.019	D;D;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0080	B;.;.
Vest4		0.40
MutPred		0.37		Loss of MoRF binding (P = 0.1516);.;.;
MVP		0.61
MPC		0.069
ClinPred		0.44	T
GERP RS		2.3
Varity_R		0.18
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147962000; hg19: chr15-44858159;