15-44562878-T-C

Position:

• chr15-44562878-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025137.4(SPG11):​c.*243A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 480,424 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (3 hom.)
• Consequence: SPG11 NM_025137.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.419

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 (HGNC:):

EIF3J (HGNC:3270): (eukaryotic translation initiation factor 3 subunit J) This gene encodes a core subunit of the eukaryotic initiation factor 3 complex, which participates in the initiation of translation by aiding in the recruitment of protein and mRNA components to the 40S ribosome. There are pseudogenes for this gene on chromosomes 1, 3, and 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-44562878-T-C is Benign according to our data. Variant chr15-44562878-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 316071.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 = 0.00635 (968/152350) while in subpopulation AFR AF= 0.0215 (894/41600). AF 95% confidence interval is 0.0203. There are 10 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.*243A>G		3_prime_UTR_variant	40/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866	c.*243A>G		3_prime_UTR_variant	40/40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 968 AN: 152232 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00717

GnomAD4 exome AF: 0.000939 AC: 308 AN: 328074 Hom.: 3 Cov.: 2 AF XY: 0.000764 AC XY: 132 AN XY: 172866

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000855

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00635 AC: 968 AN: 152350 Hom.: 10 Cov.: 32 AF XY: 0.00619 AC XY: 461 AN XY: 74500

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00157 Hom.: 3

Bravo AF: 0.00663

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2019

- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.75

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: rs116069609; hg19: chr15-44855076;