rs78183930

Variant names:

• chr15-44626492-C-T
• rs78183930
• NM_025137.4:c.2083G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025137.4(SPG11):​c.2083G>A​(p.Ala695Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0132 in 1,613,566 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (25 hom., cov: 32)
  • Exomes 𝑓: 0.013 (189 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 4.26
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008483201).
• BP6: Variant 15-44626492-C-T is Benign according to our data. Variant chr15-44626492-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1883/152174) while in subpopulation NFE AF = 0.0172 (1168/68018). AF 95% confidence interval is 0.0164. There are 25 homozygotes in GnomAd4. There are 985 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.2083G>A	p.Ala695Thr	missense	Exon 11 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.2083G>A	p.Ala695Thr	missense	Exon 11 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.2083G>A	p.Ala695Thr	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.2083G>A	p.Ala695Thr	missense	Exon 11 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.2083G>A	p.Ala695Thr	missense	Exon 11 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.2083G>A	p.Ala695Thr	missense	Exon 11 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1883 AN: 152056 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00720

GnomAD2 exomes AF: 0.0129 AC: 3224 AN: 250704 AF XY: 0.0129

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0133 AC: 19457 AN: 1461392 Hom.: 189 Cov.: 31 AF XY: 0.0133 AC XY: 9681 AN XY: 726970

African (AFR) AF: 0.00152 AC: 51 AN: 33464

American (AMR) AF: 0.00394 AC: 176 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 312 AN: 26122

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39630

South Asian (SAS) AF: 0.00290 AC: 250 AN: 86174

European-Finnish (FIN) AF: 0.0441 AC: 2355 AN: 53376

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5746

European-Non Finnish (NFE) AF: 0.0141 AC: 15629 AN: 1111810

Other (OTH) AF: 0.0110 AC: 666 AN: 60372

GnomAD4 genome AF: 0.0124 AC: 1883 AN: 152174 Hom.: 25 Cov.: 32 AF XY: 0.0132 AC XY: 985 AN XY: 74384

African (AFR) AF: 0.00258 AC: 107 AN: 41528

American (AMR) AF: 0.00451 AC: 69 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.0442 AC: 466 AN: 10554

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

European-Non Finnish (NFE) AF: 0.0172 AC: 1168 AN: 68018

Other (OTH) AF: 0.00712 AC: 15 AN: 2106

Alfa AF: 0.0144 Hom.: 81

Bravo AF: 0.00851

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.0131 AC: 113

ExAC AF: 0.0125 AC: 1517

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Hereditary spastic paraplegia 11 (6)
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.78
MPC		0.26
ClinPred		0.020	T
GERP RS		5.9
Varity_R		0.18
gMVP		0.61
Mutation Taster		=95/5	polymorphism (auto)

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: rs78183930; hg19: chr15-44918690; COSMIC: COSV105072607; COSMIC: COSV105072607;