rs201721414

Variant names:

• chr15-44565975-C-T
• rs201721414
• NM_025137.4:c.6878G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025137.4(SPG11):​c.6878G>A​(p.Arg2293Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,613,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2293W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11 O:1
• Conservation: PhyloP100: 2.35
• Publications: 5 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Illumina
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14875314).

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.6878G>A	p.Arg2293Gln	missense	Exon 38 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6734G>A	p.Arg2245Gln	missense	Exon 38 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.6539G>A	p.Arg2180Gln	missense	Exon 36 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.6878G>A	p.Arg2293Gln	missense	Exon 38 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.6539G>A	p.Arg2180Gln	missense	Exon 36 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6754+1449G>A		intron	N/A	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251124 AF XY: 0.0000958

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000200 AC: 293 AN: 1461672 Hom.: 1 Cov.: 32 AF XY: 0.000198 AC XY: 144 AN XY: 727136

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.000525 AC: 28 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.000225 AC: 250 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60382

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74402

African (AFR) AF: 0.0000482 AC: 2 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000298 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	3	-	Hereditary spastic paraplegia 11 (3)
-	1	-	Amyotrophic lateral sclerosis type 5 (1)
-	1	-	Charcot-Marie-Tooth disease axonal type 2X (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	-	Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.33
Sift	Benign	0.049	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.78
MPC		0.21
ClinPred		0.11	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.53
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201721414; hg19: chr15-44858173; COSMIC: COSV55992740; COSMIC: COSV55992740;