15-44633542-A-C

Variant names:

• chr15-44633542-A-C
• rs79708848
• NM_025137.4:c.1698T>G

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.1698T>G​(p.Asp566Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,609,150 control chromosomes in the GnomAD database, including 286 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. D566N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 31)
  • Exomes 𝑓: 0.017 (265 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.131
• Publications: 12 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=0.004883647).
• BP6: Variant 15-44633542-A-C is Benign according to our data. Variant chr15-44633542-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219609.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1810/152096) while in subpopulation NFE AF = 0.0199 (1355/67968). AF 95% confidence interval is 0.0191. There are 21 homozygotes in GnomAd4. There are 830 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.1698T>G	p.Asp566Glu	missense	Exon 8 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.1698T>G	p.Asp566Glu	missense	Exon 8 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.1698T>G	p.Asp566Glu	missense	Exon 8 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.1698T>G	p.Asp566Glu	missense	Exon 8 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.1698T>G	p.Asp566Glu	missense	Exon 8 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.1698T>G	p.Asp566Glu	missense	Exon 8 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1811 AN: 151980 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00702

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0110 AC: 2749 AN: 250768 AF XY: 0.0107

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0166 AC: 24242 AN: 1457054 Hom.: 265 Cov.: 30 AF XY: 0.0161 AC XY: 11658 AN XY: 725196

African (AFR) AF: 0.00231 AC: 77 AN: 33390

American (AMR) AF: 0.00573 AC: 256 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 116 AN: 26096

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39644

South Asian (SAS) AF: 0.00127 AC: 109 AN: 85996

European-Finnish (FIN) AF: 0.0178 AC: 953 AN: 53406

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.0197 AC: 21863 AN: 1107844

Other (OTH) AF: 0.0143 AC: 863 AN: 60248

GnomAD4 genome AF: 0.0119 AC: 1810 AN: 152096 Hom.: 21 Cov.: 31 AF XY: 0.0112 AC XY: 830 AN XY: 74372

African (AFR) AF: 0.00267 AC: 111 AN: 41508

American (AMR) AF: 0.00701 AC: 107 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.0148 AC: 156 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0199 AC: 1355 AN: 67968

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0161 Hom.: 86

Bravo AF: 0.0107

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0184 AC: 158

ExAC AF: 0.0111 AC: 1349

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0151

EpiControl AF: 0.0174

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hereditary spastic paraplegia 11 (4)
-	1	-	Amyotrophic lateral sclerosis (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	3.4
DANN	Benign	0.96
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.13
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.10
Sift	Benign	0.58	T
Sift4G	Benign	0.30	T
Polyphen		0.67	P
Vest4		0.20
MutPred		0.12		Gain of helix (P = 0.062)
MPC		0.036
ClinPred		0.021	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.12
Mutation Taster		=97/3	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: rs79708848; hg19: chr15-44925740; COSMIC: COSV55990757;