15-44585636-C-G

Variant names:

• chr15-44585636-C-G
• NM_025137.4:c.5121G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025137.4(SPG11):​c.5121G>C​(p.Glu1707Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000071 in 1,408,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.5121G>C	p.Glu1707Asp	missense_variant, splice_region_variant	Exon 29 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.5121G>C	p.Glu1707Asp	missense_variant, splice_region_variant	Exon 29 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 702754

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: 9.38e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.6	M;M;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.94	P;.;P;.
Vest4		0.42
MutPred		0.32		Loss of methylation at K1706 (P = 0.0778);Loss of methylation at K1706 (P = 0.0778);Loss of methylation at K1706 (P = 0.0778);Loss of methylation at K1706 (P = 0.0778);
MVP		0.82
MPC		0.042
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-44877834;