NM_025137.4:c.*243A>G

Variant names:

• chr15-44562878-T-C
• rs116069609
• NM_025137.4:c.*243A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.*243A>G		3_prime_UTR	Exon 40 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.*243A>G		3_prime_UTR	Exon 40 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.*243A>G		3_prime_UTR	Exon 38 of 38	NP_001153699.1	Q96JI7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.*243A>G		3_prime_UTR	Exon 40 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.*243A>G		3_prime_UTR	Exon 38 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000920242.1		c.*243A>G		3_prime_UTR	Exon 40 of 40	ENSP00000590301.1

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

African (AFR) AF: 0.0214 AC: 215 AN: 10036

American (AMR) AF: 0.00199 AC: 25 AN: 12546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10218

East Asian (EAS) AF: 0.00 AC: 0 AN: 21770

South Asian (SAS) AF: 0.00 AC: 0 AN: 35594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18730

Middle Eastern (MID) AF: 0.00206 AC: 3 AN: 1458

European-Non Finnish (NFE) AF: 0.0000855 AC: 17 AN: 198730

Other (OTH) AF: 0.00253 AC: 48 AN: 18992

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

African (AFR) AF: 0.0215 AC: 894 AN: 41600

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00210 Hom.: 4

Bravo AF: 0.00663

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 11 (2)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116069609; hg19: chr15-44855076;