NM_025137.4:c.7069C>T

Variant names:

• chr15-44564629-G-A
• rs139334167
• NM_025137.4:c.7069C>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.7069C>T​(p.Leu2357Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,770 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. L2357I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 1.39
• Publications: 7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010218263).
• BP6: Variant 15-44564629-G-A is Benign according to our data. Variant chr15-44564629-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188332.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00145 (221/152252) while in subpopulation AMR AF = 0.00471 (72/15294). AF 95% confidence interval is 0.00383. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.7069C>T	p.Leu2357Phe	missense	Exon 39 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6925C>T	p.Leu2309Phe	missense	Exon 39 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.6730C>T	p.Leu2244Phe	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.7069C>T	p.Leu2357Phe	missense	Exon 39 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.6730C>T	p.Leu2244Phe	missense	Exon 37 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6755-1328C>T		intron	N/A	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00140 AC: 352 AN: 251112 AF XY: 0.00142

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00132 AC: 1924 AN: 1461518 Hom.: 2 Cov.: 31 AF XY: 0.00132 AC XY: 960 AN XY: 727082

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.00170 AC: 76 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 292 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00124 AC: 1373 AN: 1111692

Other (OTH) AF: 0.00215 AC: 130 AN: 60382

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74430

African (AFR) AF: 0.000241 AC: 10 AN: 41548

American (AMR) AF: 0.00471 AC: 72 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00182 Hom.: 2

Bravo AF: 0.00199

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00245

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	1	Hereditary spastic paraplegia 11 (2)
-	-	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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.40
Sift	Benign	0.053	T
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.50
MVP		0.76
MPC		0.26
ClinPred		0.069	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.37
Mutation Taster		=77/23	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: rs139334167; hg19: chr15-44856827; COSMIC: COSV55991666; COSMIC: COSV55991666;