rs200573434

Variant names:

• chr15-44663632-C-T
• rs200573434
• NM_025137.4:c.16G>A

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.16G>A​(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,595,546 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 0.341
• Publications: 4 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=0.0047059953).
• BP6: Variant 15-44663632-C-T is Benign according to our data. Variant chr15-44663632-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216771.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00138 (210/152370) while in subpopulation NFE AF = 0.00215 (146/68030). AF 95% confidence interval is 0.00186. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.16G>A	p.Gly6Arg	missense	Exon 1 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.16G>A	p.Gly6Arg	missense	Exon 1 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.16G>A	p.Gly6Arg	missense	Exon 1 of 38	NP_001153699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.16G>A	p.Gly6Arg	missense	Exon 1 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.16G>A	p.Gly6Arg	missense	Exon 1 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.16G>A	p.Gly6Arg	missense	Exon 1 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152252 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00129 AC: 276 AN: 214166 AF XY: 0.00126

Gnomad AFR exome AF: 0.000827

Gnomad AMR exome AF: 0.000701

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0000587

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.00213 AC: 3075 AN: 1443176 Hom.: 4 Cov.: 32 AF XY: 0.00209 AC XY: 1501 AN XY: 717648

African (AFR) AF: 0.000539 AC: 18 AN: 33374

American (AMR) AF: 0.000687 AC: 30 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.0000776 AC: 2 AN: 25770

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39470

South Asian (SAS) AF: 0.000141 AC: 12 AN: 84912

European-Finnish (FIN) AF: 0.000742 AC: 31 AN: 41794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00257 AC: 2851 AN: 1108474

Other (OTH) AF: 0.00215 AC: 129 AN: 59962

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152370 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74514

African (AFR) AF: 0.000866 AC: 36 AN: 41594

American (AMR) AF: 0.00124 AC: 19 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00153

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00131 AC: 11

ExAC AF: 0.00138 AC: 166

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Hereditary spastic paraplegia 11 (2)
-	1	-	Amyotrophic lateral sclerosis (1)
-	1	-	Amyotrophic lateral sclerosis type 5 (1)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.7
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.34
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.13
Sift	Benign	0.22	T
Sift4G	Benign	0.074	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.32		Gain of MoRF binding (P = 0.0266)
MVP		0.67
MPC		0.041
ClinPred		0.0068	T
GERP RS		2.5
PromoterAI		-0.0083	Neutral
Varity_R		0.036
gMVP		0.23
Mutation Taster		=94/6	polymorphism

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: rs200573434; hg19: chr15-44955830; COSMIC: COSV55995618; COSMIC: COSV55995618;