rs3759874

Variant names:

• chr15-44651600-G-A
• rs3759874
• NM_025137.4:c.1347C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025137.4(SPG11):​c.1347C>T​(p.Thr449Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,178 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 32)
  • Exomes 𝑓: 0.010 (298 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.287
• Publications: 7 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-44651600-G-A is Benign according to our data. Variant chr15-44651600-G-A is described in ClinVar as Benign. ClinVar VariationId is 130363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.287 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.1347C>T	p.Thr449Thr	synonymous	Exon 6 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.1347C>T	p.Thr449Thr	synonymous	Exon 6 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.1347C>T	p.Thr449Thr	synonymous	Exon 6 of 38	NP_001153699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.1347C>T	p.Thr449Thr	synonymous	Exon 6 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.1347C>T	p.Thr449Thr	synonymous	Exon 6 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.1347C>T	p.Thr449Thr	synonymous	Exon 6 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2199 AN: 152186 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0963

Gnomad SAS AF: 0.0484

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.0184 AC: 4635 AN: 251470 AF XY: 0.0185

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0947

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0102 AC: 14867 AN: 1461874 Hom.: 298 Cov.: 35 AF XY: 0.0109 AC XY: 7910 AN XY: 727238

African (AFR) AF: 0.0158 AC: 528 AN: 33480

American (AMR) AF: 0.00293 AC: 131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 170 AN: 26136

East Asian (EAS) AF: 0.0738 AC: 2931 AN: 39698

South Asian (SAS) AF: 0.0364 AC: 3142 AN: 86256

European-Finnish (FIN) AF: 0.0320 AC: 1711 AN: 53420

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00489 AC: 5437 AN: 1111996

Other (OTH) AF: 0.0130 AC: 785 AN: 60396

GnomAD4 genome AF: 0.0145 AC: 2214 AN: 152304 Hom.: 57 Cov.: 32 AF XY: 0.0174 AC XY: 1298 AN XY: 74480

African (AFR) AF: 0.0149 AC: 618 AN: 41562

American (AMR) AF: 0.00346 AC: 53 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.0966 AC: 501 AN: 5188

South Asian (SAS) AF: 0.0483 AC: 233 AN: 4826

European-Finnish (FIN) AF: 0.0353 AC: 374 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00537 AC: 365 AN: 68024

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00638 Hom.: 4

Bravo AF: 0.0128

Asia WGS AF: 0.0750 AC: 261 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00480

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Hereditary spastic paraplegia 11 (3)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.6
DANN	Benign	0.27
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs3759874; hg19: chr15-44943798; COSMIC: COSV55998769;