rs76389165

chr15-44598705-T-Cchr15-44598705-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025137.4(SPG11):c.3818A>G(p.Lys1273Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,614,194 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. K1273T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (26 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 3.15

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072818696).
• BP6: Variant 15-44598705-T-C is Benign according to our data. Variant chr15-44598705-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130365.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=4, Uncertain_significance=1}. Variant chr15-44598705-T-C is described in Lovd as [Likely_benign]. Variant chr15-44598705-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00791 (1205/152312) while in subpopulation AFR AF= 0.025 (1038/41568). AF 95% confidence interval is 0.0237. There are 16 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.3818A>G	p.Lys1273Arg	missense_variant	22/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.3818A>G	p.Lys1273Arg	missense_variant	22/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1203 AN: 152194 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00269 AC: 675 AN: 251288 Hom.: 11 AF XY: 0.00231 AC XY: 314 AN XY: 135792

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000872

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00144 AC: 2110 AN: 1461882 Hom.: 26 Cov.: 31 AF XY: 0.00136 AC XY: 989 AN XY: 727242

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00791 AC: 1205 AN: 152312 Hom.: 16 Cov.: 32 AF XY: 0.00718 AC XY: 535 AN XY: 74488

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00182 Hom.: 6

Bravo AF: 0.00955

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0248 AC: 109

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00311 AC: 377

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SPG11: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 02, 2018	- -

Hereditary spastic paraplegia 11 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 21, 2017	- -

Hereditary spastic paraplegia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 14, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.;T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;D;D;D
MetaRNN	Benign	0.0073	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L;L;.;L
MutationTaster	Benign	0.75	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.42	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.34	T;T;T;D
Polyphen		0.12	B;.;P;.
Vest4		0.32
MVP		0.79
MPC		0.033
ClinPred		0.032	T
GERP RS		6.0
Varity_R		0.096
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs76389165; hg19: chr15-44890903;