chr15-44563256-C-T

Variant names:

• chr15-44563256-C-T
• rs61732733
• NM_025137.4:c.7197G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_025137.4(SPG11):​c.7197G>A​(p.Lys2399Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,613,934 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0077 (14 hom., cov: 32)
  • Exomes 𝑓: 0.013 (178 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.43
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-44563256-C-T is Benign according to our data. Variant chr15-44563256-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220388.
• BP7: Synonymous conserved (PhyloP=2.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00771 (1175/152332) while in subpopulation NFE AF = 0.0148 (1009/68032). AF 95% confidence interval is 0.0141. There are 14 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.7197G>A	p.Lys2399Lys	synonymous	Exon 40 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.7053G>A	p.Lys2351Lys	synonymous	Exon 40 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.6858G>A	p.Lys2286Lys	synonymous	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.7197G>A	p.Lys2399Lys	synonymous	Exon 40 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.6858G>A	p.Lys2286Lys	synonymous	Exon 38 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.*2G>A		3_prime_UTR	Exon 37 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1175 AN: 152214 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00674 AC: 1695 AN: 251384 AF XY: 0.00661

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.0132 AC: 19342 AN: 1461602 Hom.: 178 Cov.: 30 AF XY: 0.0126 AC XY: 9164 AN XY: 727138

African (AFR) AF: 0.00242 AC: 81 AN: 33478

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86252

European-Finnish (FIN) AF: 0.00180 AC: 96 AN: 53414

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.0166 AC: 18488 AN: 1111774

Other (OTH) AF: 0.00767 AC: 463 AN: 60386

GnomAD4 genome AF: 0.00771 AC: 1175 AN: 152332 Hom.: 14 Cov.: 32 AF XY: 0.00682 AC XY: 508 AN XY: 74494

African (AFR) AF: 0.00262 AC: 109 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1009 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.0114 Hom.: 7

Bravo AF: 0.00740

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0116

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	Hereditary spastic paraplegia 11 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		2.4
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: rs61732733; hg19: chr15-44855454; COSMIC: COSV99969970; COSMIC: COSV99969970;