rs139887370

Variant names:

• chr15-44596919-T-C
• rs139887370
• NM_025137.4:c.4026A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_025137.4(SPG11):​c.4026A>G​(p.Gln1342Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0007 in 1,613,968 control chromosomes in the GnomAD database, including 5 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 0.00066 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (4 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.287
• Publications: 1 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]

SPG11 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Illumina, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2X

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-44596919-T-C is Benign according to our data. Variant chr15-44596919-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241594.
• BP7: Synonymous conserved (PhyloP=0.287 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000664 (101/152132) while in subpopulation NFE AF = 0.000985 (67/67998). AF 95% confidence interval is 0.000795. There are 1 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.4026A>G	p.Gln1342Gln	synonymous	Exon 24 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.4026A>G	p.Gln1342Gln	synonymous	Exon 24 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.4026A>G	p.Gln1342Gln	synonymous	Exon 24 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.4026A>G	p.Gln1342Gln	synonymous	Exon 24 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.4026A>G	p.Gln1342Gln	synonymous	Exon 24 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.4026A>G	p.Gln1342Gln	synonymous	Exon 24 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152016 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00246

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000964

GnomAD2 exomes AF: 0.000565 AC: 142 AN: 251328 AF XY: 0.000486

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000703 AC: 1028 AN: 1461836 Hom.: 4 Cov.: 33 AF XY: 0.000663 AC XY: 482 AN XY: 727212

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.00182 AC: 97 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000789 AC: 877 AN: 1111984

Other (OTH) AF: 0.000546 AC: 33 AN: 60390

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152132 Hom.: 1 Cov.: 31 AF XY: 0.000524 AC XY: 39 AN XY: 74394

African (AFR) AF: 0.0000964 AC: 4 AN: 41514

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00246 AC: 26 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 67998

Other (OTH) AF: 0.000954 AC: 2 AN: 2096

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.000465

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	Hereditary spastic paraplegia 11 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.2
DANN	Benign	0.82
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139887370; hg19: chr15-44889117;