rs150823040

Variant names:

• chr15-44584365-C-T
• rs150823040
• NM_025137.4:c.5315G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_025137.4(SPG11):​c.5315G>A​(p.Arg1772His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,611,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R1772C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 1.22
• Publications: 3 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10280505).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000204 (31/152310) while in subpopulation SAS AF = 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.5315G>A	p.Arg1772His	missense	Exon 30 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.5171G>A	p.Arg1724His	missense	Exon 30 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.5315G>A	p.Arg1772His	missense	Exon 30 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.5315G>A	p.Arg1772His	missense	Exon 30 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.5315G>A	p.Arg1772His	missense	Exon 30 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.5315G>A	p.Arg1772His	missense	Exon 30 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000156 AC: 39 AN: 250066 AF XY: 0.000126

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000284 AC: 415 AN: 1459010 Hom.: 1 Cov.: 32 AF XY: 0.000294 AC XY: 213 AN XY: 725436

African (AFR) AF: 0.000270 AC: 9 AN: 33324

American (AMR) AF: 0.0000674 AC: 3 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39660

South Asian (SAS) AF: 0.000674 AC: 58 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000295 AC: 328 AN: 1110040

Other (OTH) AF: 0.000199 AC: 12 AN: 60226

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74476

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.14
MVP		0.76
MPC		0.075
ClinPred		0.082	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.12
gMVP		0.43
Mutation Taster		=82/18	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: rs150823040; hg19: chr15-44876563; COSMIC: COSV99969019; COSMIC: COSV99969019;