rs80338869

Positions:

• chr15-44564675-G-A
• chr15-44564675-G-C
• chr15-44564675-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_025137.4(SPG11):​c.7023C>T​(p.Tyr2341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,613,970 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.019 (31 hom., cov: 32)
  • Exomes 𝑓: 0.026 (624 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.05

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 -9 ACMG points.

• BP6: Variant 15-44564675-G-A is Benign according to our data. Variant chr15-44564675-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41357.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr15-44564675-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0189 (2878/152250) while in subpopulation NFE AF= 0.0286 (1944/68014). AF 95% confidence interval is 0.0275. There are 31 homozygotes in gnomad4. There are 1309 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.7023C>T	p.Tyr2341=	synonymous_variant	39/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.7023C>T	p.Tyr2341=	synonymous_variant	39/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2879 AN: 152132 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0205 AC: 5158 AN: 251064 Hom.: 73 AF XY: 0.0209 AC XY: 2837 AN XY: 135784

Gnomad AFR exome AF: 0.00490

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0317

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0167

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0265 AC: 38725 AN: 1461720 Hom.: 624 Cov.: 32 AF XY: 0.0265 AC XY: 19252 AN XY: 727174

Gnomad4 AFR exome AF: 0.00445

Gnomad4 AMR exome AF: 0.0202

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0176

Gnomad4 FIN exome AF: 0.00549

Gnomad4 NFE exome AF: 0.0298

Gnomad4 OTH exome AF: 0.0277

GnomAD4 genome AF: 0.0189 AC: 2878 AN: 152250 Hom.: 31 Cov.: 32 AF XY: 0.0176 AC XY: 1309 AN XY: 74452

Gnomad4 AFR AF: 0.00518

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0182 Hom.: 29

Bravo AF: 0.0197

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0312

EpiControl AF: 0.0287

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2016	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. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338869; hg19: chr15-44856873;