rs1555448900

Variant names:

• chr15-44584254-T-C
• rs1555448900
• NM_025137.4:c.5426A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025137.4(SPG11):​c.5426A>G​(p.His1809Arg) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Illumina, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2X

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12720188).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.5426A>G	p.His1809Arg	missense	Exon 30 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.5282A>G	p.His1761Arg	missense	Exon 30 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.5426A>G	p.His1809Arg	missense	Exon 30 of 38	NP_001153699.1	Q96JI7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.5426A>G	p.His1809Arg	missense	Exon 30 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.5426A>G	p.His1809Arg	missense	Exon 30 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.5426A>G	p.His1809Arg	missense	Exon 30 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.45	T
Polyphen		0.016	B
Vest4		0.15
MutPred		0.41		Gain of MoRF binding (P = 0.0079)
MVP		0.69
MPC		0.047
ClinPred		0.16	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.22

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

Other links and lift over

dbSNP: rs1555448900; hg19: chr15-44876452;