rs111347025

Variant names:

• chr15-44615364-T-C
• rs111347025
• NM_025137.4:c.3037A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025137.4(SPG11):​c.3037A>G​(p.Lys1013Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,368 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0095 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (129 hom.)
• Consequence: SPG11 NM_025137.4 missense, splice_region
• Scores: Splicing: ADA: 0.5875
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.67
• Publications: 14 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009679407).
• BP6: Variant 15-44615364-T-C is Benign according to our data. Variant chr15-44615364-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194676.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00946 (1441/152346) while in subpopulation AMR AF = 0.0148 (227/15300). AF 95% confidence interval is 0.0133. There are 8 homozygotes in GnomAd4. There are 716 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.3037A>G	p.Lys1013Glu	missense splice_region	Exon 16 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.3037A>G	p.Lys1013Glu	missense splice_region	Exon 16 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.3037A>G	p.Lys1013Glu	missense splice_region	Exon 16 of 38	NP_001153699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.3037A>G	p.Lys1013Glu	missense splice_region	Exon 16 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.3037A>G	p.Lys1013Glu	missense splice_region	Exon 16 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.3037A>G	p.Lys1013Glu	missense splice_region	Exon 16 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00946 AC: 1440 AN: 152228 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0102 AC: 2564 AN: 251164 AF XY: 0.0107

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0116 AC: 16941 AN: 1461022 Hom.: 129 Cov.: 31 AF XY: 0.0118 AC XY: 8553 AN XY: 726848

African (AFR) AF: 0.00212 AC: 71 AN: 33466

American (AMR) AF: 0.0115 AC: 513 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 411 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00818 AC: 705 AN: 86220

European-Finnish (FIN) AF: 0.00139 AC: 74 AN: 53330

Middle Eastern (MID) AF: 0.0126 AC: 67 AN: 5336

European-Non Finnish (NFE) AF: 0.0130 AC: 14455 AN: 1111812

Other (OTH) AF: 0.0107 AC: 645 AN: 60338

GnomAD4 genome AF: 0.00946 AC: 1441 AN: 152346 Hom.: 8 Cov.: 32 AF XY: 0.00961 AC XY: 716 AN XY: 74498

African (AFR) AF: 0.00245 AC: 102 AN: 41588

American (AMR) AF: 0.0148 AC: 227 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 914 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0128 Hom.: 52

Bravo AF: 0.0105

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.00992 AC: 1205

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0169

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	Hereditary spastic paraplegia 11 (6)
-	-	5	not specified (5)
-	1	-	Amyotrophic lateral sclerosis (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.12
Sift	Benign	0.44	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.25
MPC		0.047
ClinPred		0.0030	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.27
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.37
SpliceAI score (max)		0.10		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: rs111347025; hg19: chr15-44907562;