rs116807842

Variant names:

• chr15-44589348-A-G
• rs116807842
• NM_025137.4:c.4810T>C

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.4810T>C​(p.Phe1604Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,178 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (26 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.33
• 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• 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=0.007002324).
• BP6: Variant 15-44589348-A-G is Benign according to our data. Variant chr15-44589348-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00872 (1328/152352) while in subpopulation AFR AF = 0.03 (1248/41574). AF 95% confidence interval is 0.0286. There are 20 homozygotes in GnomAd4. There are 622 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.4810T>C	p.Phe1604Leu	missense	Exon 28 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.4810T>C	p.Phe1604Leu	missense	Exon 28 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.4810T>C	p.Phe1604Leu	missense	Exon 28 of 38	NP_001153699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.4810T>C	p.Phe1604Leu	missense	Exon 28 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.4810T>C	p.Phe1604Leu	missense	Exon 28 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.4810T>C	p.Phe1604Leu	missense	Exon 28 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1324 AN: 152234 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.000132

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00216 AC: 544 AN: 251342 AF XY: 0.00165

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000986 AC: 1442 AN: 1461826 Hom.: 26 Cov.: 31 AF XY: 0.000877 AC XY: 638 AN XY: 727226

African (AFR) AF: 0.0348 AC: 1164 AN: 33474

American (AMR) AF: 0.00121 AC: 54 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111962

Other (OTH) AF: 0.00220 AC: 133 AN: 60394

GnomAD4 genome AF: 0.00872 AC: 1328 AN: 152352 Hom.: 20 Cov.: 32 AF XY: 0.00835 AC XY: 622 AN XY: 74506

African (AFR) AF: 0.0300 AC: 1248 AN: 41574

American (AMR) AF: 0.00340 AC: 52 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68040

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00381 Hom.: 16

Bravo AF: 0.0101

ESP6500AA AF: 0.0264 AC: 116

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary spastic paraplegia 11 (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	0.61
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.75
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.027	B
Vest4		0.35
MutPred		0.61		Loss of ubiquitination at K1607 (P = 0.073)
MVP		0.74
MPC		0.043
ClinPred		0.010	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.24
Mutation Taster		=96/4	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: rs116807842; hg19: chr15-44881546;