rs147550048

Positions:

• chr15-44589420-A-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.4744-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,030 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: SPG11 NM_025137.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004736
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: -0.877

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 (BayesDel_noAF=-0.87).
• BP6: Variant 15-44589420-A-G is Benign according to our data. Variant chr15-44589420-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}. Variant chr15-44589420-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00147 (224/152346) while in subpopulation NFE AF= 0.00269 (183/68040). AF 95% confidence interval is 0.00237. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.4744-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.4744-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_025137.4	ENSP00000261866

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00123 AC: 308 AN: 251156 Hom.: 0 AF XY: 0.00123 AC XY: 167 AN XY: 135728

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00194 AC: 2840 AN: 1461684 Hom.: 7 Cov.: 31 AF XY: 0.00193 AC XY: 1404 AN XY: 727158

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74502

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00123

EpiCase AF: 0.00202

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SPG11: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	- -

Hereditary spastic paraplegia 11 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.37
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0060
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: rs147550048; hg19: chr15-44881618;