NM_025137.4:c.2075T>C

Variant names:

• chr15-44626500-A-G
• rs144012151
• NM_025137.4:c.2075T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_025137.4(SPG11):​c.2075T>C​(p.Ile692Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 5.46
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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.2075T>C	p.Ile692Thr	missense	Exon 11 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.2075T>C	p.Ile692Thr	missense	Exon 11 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.2075T>C	p.Ile692Thr	missense	Exon 11 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.2075T>C	p.Ile692Thr	missense	Exon 11 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.2075T>C	p.Ile692Thr	missense	Exon 11 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.2075T>C	p.Ile692Thr	missense	Exon 11 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 250536 AF XY: 0.000111

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000203 AC: 297 AN: 1461368 Hom.: 0 Cov.: 31 AF XY: 0.000194 AC XY: 141 AN XY: 726958

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000264 AC: 294 AN: 1111856

Other (OTH) AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74366

African (AFR) AF: 0.000121 AC: 5 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000562 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary spastic paraplegia 11 (3)
-	3	-	not provided (3)
-	1	-	Amyotrophic lateral sclerosis type 5 (1)
-	1	-	Charcot-Marie-Tooth disease axonal type 2X (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.065
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.55
Sift	Benign	0.055	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.81
MPC		0.27
ClinPred		0.31	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.55
Mutation Taster		=89/11	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: rs144012151; hg19: chr15-44918698;