15-44585636-C-A

Variant names:

• chr15-44585636-C-A
• rs145643238
• NM_025137.4:c.5121G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_Strong BS1_Supporting BS2

The NM_025137.4(SPG11):​c.5121G>T​(p.Glu1707Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000764 in 1,559,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. E1707K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: SPG11 NM_025137.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:1 O:1
• Conservation: PhyloP100: 5.98
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00096 (145/150986) while in subpopulation AMR AF = 0.00463 (70/15122). AF 95% confidence interval is 0.00376. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 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.5121G>T	p.Glu1707Asp	missense splice_region	Exon 29 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.5121G>T	p.Glu1707Asp	missense splice_region	Exon 29 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.5121G>T	p.Glu1707Asp	missense splice_region	Exon 29 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.5121G>T	p.Glu1707Asp	missense splice_region	Exon 29 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.5121G>T	p.Glu1707Asp	missense splice_region	Exon 29 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.5121G>T	p.Glu1707Asp	missense splice_region	Exon 29 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 145 AN: 150880 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000767

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.000688 AC: 172 AN: 249886 AF XY: 0.000732

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.000737

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000743 AC: 1046 AN: 1408214 Hom.: 2 Cov.: 32 AF XY: 0.000727 AC XY: 511 AN XY: 702746

African (AFR) AF: 0.000156 AC: 5 AN: 32064

American (AMR) AF: 0.000944 AC: 42 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25666

East Asian (EAS) AF: 0.00 AC: 0 AN: 38950

South Asian (SAS) AF: 0.000833 AC: 71 AN: 85250

European-Finnish (FIN) AF: 0.00116 AC: 61 AN: 52388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 0.000776 AC: 827 AN: 1065558

Other (OTH) AF: 0.000684 AC: 40 AN: 58478

GnomAD4 genome AF: 0.000960 AC: 145 AN: 150986 Hom.: 0 Cov.: 30 AF XY: 0.00115 AC XY: 85 AN XY: 73762

African (AFR) AF: 0.000169 AC: 7 AN: 41318

American (AMR) AF: 0.00463 AC: 70 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4780

European-Finnish (FIN) AF: 0.00109 AC: 11 AN: 10122

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

European-Non Finnish (NFE) AF: 0.000767 AC: 52 AN: 67756

Other (OTH) AF: 0.00144 AC: 3 AN: 2082

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	9	-	not provided (9)
-	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	-	Intellectual disability (1)
-	-	1	not specified (1)
-	1	-	SPG11-related disorder (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	Uncertain	0.52
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.035	D
Polyphen		0.94	P
Vest4		0.42
MutPred		0.32		Loss of methylation at K1706 (P = 0.0778)
MVP		0.82
MPC		0.042
ClinPred		0.12	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.40
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

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

Other links and lift over

dbSNP: rs145643238; hg19: chr15-44877834;