chr15-44585824-G-T

Position:

• chr15-44585824-G-T

Variant summary

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

The NM_025137.4(SPG11):​c.4933C>A​(p.Leu1645Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.4933C>A	p.Leu1645Ile	missense_variant	29/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.4933C>A	p.Leu1645Ile	missense_variant	29/40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251300 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135814

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.9	M;M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.19	N;N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.016	D;T;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.46
MutPred		0.50		Gain of methylation at K1641 (P = 0.0528);Gain of methylation at K1641 (P = 0.0528);Gain of methylation at K1641 (P = 0.0528);Gain of methylation at K1641 (P = 0.0528);
MVP		0.81
MPC		0.26
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.19
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: rs147735958; hg19: chr15-44878022;