15-44620410-GA-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_025137.4(SPG11):c.2621-8_2621-7insT 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 0.000722 in 1,582,566 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: SPG11 NM_025137.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.681

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 -16 ACMG points.

• BP6: Variant 15-44620410-G-GA is Benign according to our data. Variant chr15-44620410-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 413993.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 = 0.00358 (542/151388) while in subpopulation AFR AF= 0.0122 (503/41296). AF 95% confidence interval is 0.0113. There are 4 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.2621-8_2621-7insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.2621-8_2621-7insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 543 AN: 151274 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00110 AC: 259 AN: 234770 Hom.: 2 AF XY: 0.000894 AC XY: 114 AN XY: 127470

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00146

Gnomad SAS exome AF: 0.0000713

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000938

Gnomad OTH exome AF: 0.000354

GnomAD4 exome AF: 0.000419 AC: 600 AN: 1431178 Hom.: 3 Cov.: 27 AF XY: 0.000386 AC XY: 275 AN XY: 713172

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000559

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000862

Gnomad4 OTH exome AF: 0.000947

GnomAD4 genome AF: 0.00358 AC: 542 AN: 151388 Hom.: 4 Cov.: 32 AF XY: 0.00344 AC XY: 254 AN XY: 73920

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.00191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.000475

Bravo AF: 0.00408

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SPG11: BP4, BS1, BS2 -

Hereditary spastic paraplegia 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

SPG11-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 09, 2021

- -

Amyotrophic lateral sclerosis type 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Charcot-Marie-Tooth disease axonal type 2X Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs577083743; hg19: chr15-44912608;