rs76116949

Variant names:

• chr15-44563197-T-C
• rs76116949
• NM_025137.4:c.7256A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025137.4(SPG11):​c.7256A>G​(p.Lys2419Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,614,190 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (44 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.46
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036320686).
• BP6: Variant 15-44563197-T-C is Benign according to our data. Variant chr15-44563197-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241599.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1782/152346) while in subpopulation AFR AF = 0.0411 (1710/41574). AF 95% confidence interval is 0.0395. There are 43 homozygotes in GnomAd4. There are 828 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.7256A>G	p.Lys2419Arg	missense	Exon 40 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.7112A>G	p.Lys2371Arg	missense	Exon 40 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.6917A>G	p.Lys2306Arg	missense	Exon 38 of 38	NP_001153699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.7256A>G	p.Lys2419Arg	missense	Exon 40 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.6917A>G	p.Lys2306Arg	missense	Exon 38 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.*61A>G		3_prime_UTR	Exon 37 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1768 AN: 152228 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00305 AC: 766 AN: 251404 AF XY: 0.00235

Gnomad AFR exome AF: 0.0428

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00123 AC: 1801 AN: 1461844 Hom.: 44 Cov.: 31 AF XY: 0.00110 AC XY: 798 AN XY: 727224

African (AFR) AF: 0.0438 AC: 1468 AN: 33478

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111990

Other (OTH) AF: 0.00277 AC: 167 AN: 60394

GnomAD4 genome AF: 0.0117 AC: 1782 AN: 152346 Hom.: 43 Cov.: 32 AF XY: 0.0111 AC XY: 828 AN XY: 74504

African (AFR) AF: 0.0411 AC: 1710 AN: 41574

American (AMR) AF: 0.00333 AC: 51 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00381 Hom.: 31

Bravo AF: 0.0135

ESP6500AA AF: 0.0378 AC: 166

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00381 AC: 463

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spastic paraplegia 11 (5)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	1	-	Amyotrophic lateral sclerosis (1)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.23
Sift	Benign	0.31	T
Sift4G	Uncertain	0.055	T
Polyphen		0.99	D
Vest4		0.68
MVP		0.72
MPC		0.19
ClinPred		0.0099	T
GERP RS		2.3
Varity_R		0.029
gMVP		0.17
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: rs76116949; hg19: chr15-44855395;