rs77697105

Variant names:

• chr15-44651839-C-T
• rs77697105
• NM_025137.4:c.1108G>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.1108G>A​(p.Glu370Lys) variant causes a missense change. The variant allele was found at a frequency of 0.018 in 1,613,924 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 32)
  • Exomes 𝑓: 0.018 (311 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 3.68
• Publications: 17 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=0.0067484677).
• BP6: Variant 15-44651839-C-T is Benign according to our data. Variant chr15-44651839-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220565.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 = 0.0163 (2483/152252) while in subpopulation NFE AF = 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 33 homozygotes in GnomAd4. There are 1251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.1108G>A	p.Glu370Lys	missense	Exon 6 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.1108G>A	p.Glu370Lys	missense	Exon 6 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.1108G>A	p.Glu370Lys	missense	Exon 6 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.1108G>A	p.Glu370Lys	missense	Exon 6 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.1108G>A	p.Glu370Lys	missense	Exon 6 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.1108G>A	p.Glu370Lys	missense	Exon 6 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2483 AN: 152134 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0171 AC: 4280 AN: 250764 AF XY: 0.0174

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0182 AC: 26581 AN: 1461672 Hom.: 311 Cov.: 35 AF XY: 0.0183 AC XY: 13321 AN XY: 727094

African (AFR) AF: 0.00296 AC: 99 AN: 33480

American (AMR) AF: 0.00801 AC: 358 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 625 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00667 AC: 575 AN: 86258

European-Finnish (FIN) AF: 0.0435 AC: 2320 AN: 53340

Middle Eastern (MID) AF: 0.0288 AC: 166 AN: 5768

European-Non Finnish (NFE) AF: 0.0193 AC: 21419 AN: 1111884

Other (OTH) AF: 0.0168 AC: 1017 AN: 60394

GnomAD4 genome AF: 0.0163 AC: 2483 AN: 152252 Hom.: 33 Cov.: 32 AF XY: 0.0168 AC XY: 1251 AN XY: 74436

African (AFR) AF: 0.00363 AC: 151 AN: 41550

American (AMR) AF: 0.00942 AC: 144 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 71 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4820

European-Finnish (FIN) AF: 0.0440 AC: 466 AN: 10596

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1560 AN: 68024

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0198 Hom.: 115

Bravo AF: 0.0125

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0204 AC: 175

ExAC AF: 0.0167 AC: 2022

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0188

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Hereditary spastic paraplegia 11 (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	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0067	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.029	D
Sift4G	Benign	0.31	T
Polyphen		0.38	B
Vest4		0.35
MPC		0.27
ClinPred		0.016	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.35
Mutation Taster		=99/1	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: rs77697105; hg19: chr15-44944037;