NM_025137.4:c.6258G>T

Variant names:

• chr15-44572768-C-A
• rs150761878
• NM_025137.4:c.6258G>T

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.6258G>T​(p.Leu2086Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,614,044 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2086L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (48 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: -0.0190
• 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: 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 (BayesDel_noAF=-0.61).
• BP6: Variant 15-44572768-C-A is Benign according to our data. Variant chr15-44572768-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130366.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (787/152216) while in subpopulation NFE AF = 0.00604 (411/68016). AF 95% confidence interval is 0.00556. There are 6 homozygotes in GnomAd4. There are 444 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.6258G>T	p.Leu2086Leu	synonymous	Exon 33 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6114G>T	p.Leu2038Leu	synonymous	Exon 33 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.5919G>T	p.Leu1973Leu	synonymous	Exon 31 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.6258G>T	p.Leu2086Leu	synonymous	Exon 33 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.5919G>T	p.Leu1973Leu	synonymous	Exon 31 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.6258G>T	p.Leu2086Leu	synonymous	Exon 33 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 786 AN: 152098 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00656 AC: 1650 AN: 251484 AF XY: 0.00633

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00587 AC: 8578 AN: 1461828 Hom.: 48 Cov.: 32 AF XY: 0.00563 AC XY: 4093 AN XY: 727224

African (AFR) AF: 0.000866 AC: 29 AN: 33478

American (AMR) AF: 0.00593 AC: 265 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86256

European-Finnish (FIN) AF: 0.0264 AC: 1408 AN: 53420

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.00581 AC: 6458 AN: 1111952

Other (OTH) AF: 0.00498 AC: 301 AN: 60396

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152216 Hom.: 6 Cov.: 31 AF XY: 0.00597 AC XY: 444 AN XY: 74416

African (AFR) AF: 0.000963 AC: 40 AN: 41536

American (AMR) AF: 0.00412 AC: 63 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.0234 AC: 248 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00604 AC: 411 AN: 68016

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00435 Hom.: 2

Bravo AF: 0.00369

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00634

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.4
DANN	Benign	0.63
PhyloP100		-0.019
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	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: rs150761878; hg19: chr15-44864966; COSMIC: COSV99969966; COSMIC: COSV99969966;