rs150571352

Variant names:

• chr15-44564566-A-G
• rs150571352
• NM_025137.4:c.7132T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_025137.4(SPG11):​c.7132T>C​(p.Phe2378Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 4.81
• 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: 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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000133 (195/1461702) while in subpopulation MID AF = 0.00663 (38/5728). AF 95% confidence interval is 0.00497. There are 0 homozygotes in GnomAdExome4. There are 108 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.7132T>C	p.Phe2378Leu	missense	Exon 39 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6988T>C	p.Phe2330Leu	missense	Exon 39 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.6793T>C	p.Phe2265Leu	missense	Exon 37 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.7132T>C	p.Phe2378Leu	missense	Exon 39 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.6793T>C	p.Phe2265Leu	missense	Exon 37 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6755-1265T>C		intron	N/A	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251000 AF XY: 0.000206

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727160

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.000380 AC: 17 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00663 AC: 38 AN: 5728

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111922

Other (OTH) AF: 0.000182 AC: 11 AN: 60382

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00633 AC: 2 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.30		Gain of disorder (P = 0.0827)
MVP		0.76
MPC		0.18
ClinPred		0.10	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.49
Mutation Taster		=47/53	disease causing

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: rs150571352; hg19: chr15-44856764;