chr15-44567546-C-A

Position:

• chr15-44567546-C-A

Variant summary

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

The NM_025137.4(SPG11):​c.6632G>T​(p.Arg2211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2211H) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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=0.0917384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.6632G>T	p.Arg2211Leu	missense_variant	36/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.6632G>T	p.Arg2211Leu	missense_variant	36/40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151944 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151944 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74216

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.025	T;.;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.092	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	N;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.11	B;.;B;.
Vest4		0.47
MutPred		0.36		Gain of ubiquitination at K2208 (P = 0.0436);.;Gain of ubiquitination at K2208 (P = 0.0436);.;
MVP		0.42
MPC		0.043
ClinPred		0.35	T
GERP RS		3.1
Varity_R		0.062
gMVP		0.37

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: rs144165094; hg19: chr15-44859744;