rs36014111

Variant names:

• chr15-44608477-C-T
• rs36014111
• NM_025137.4:c.3420G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_025137.4(SPG11):​c.3420G>A​(p.Leu1140Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,613,804 control chromosomes in the GnomAD database, including 1,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (123 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1823 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.150
• 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]

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 15-44608477-C-T is Benign according to our data. Variant chr15-44608477-C-T is described in ClinVar as Benign. ClinVar VariationId is 41305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0524 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.3420G>A	p.Leu1140Leu	synonymous	Exon 19 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.3420G>A	p.Leu1140Leu	synonymous	Exon 19 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.3420G>A	p.Leu1140Leu	synonymous	Exon 19 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.3420G>A	p.Leu1140Leu	synonymous	Exon 19 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.3420G>A	p.Leu1140Leu	synonymous	Exon 19 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.3420G>A	p.Leu1140Leu	synonymous	Exon 19 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4943 AN: 152082 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0356 AC: 8938 AN: 251396 AF XY: 0.0352

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.0726

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0540

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0457 AC: 66724 AN: 1461604 Hom.: 1823 Cov.: 31 AF XY: 0.0445 AC XY: 32327 AN XY: 727100

African (AFR) AF: 0.00702 AC: 235 AN: 33480

American (AMR) AF: 0.0246 AC: 1100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0728 AC: 1903 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00480 AC: 414 AN: 86258

European-Finnish (FIN) AF: 0.0363 AC: 1940 AN: 53416

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.0528 AC: 58667 AN: 1111750

Other (OTH) AF: 0.0398 AC: 2406 AN: 60390

GnomAD4 genome AF: 0.0325 AC: 4943 AN: 152200 Hom.: 123 Cov.: 32 AF XY: 0.0305 AC XY: 2268 AN XY: 74404

African (AFR) AF: 0.00864 AC: 359 AN: 41538

American (AMR) AF: 0.0291 AC: 445 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 263 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.0317 AC: 336 AN: 10584

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3357 AN: 68022

Other (OTH) AF: 0.0299 AC: 63 AN: 2110

Alfa AF: 0.0463 Hom.: 391

Bravo AF: 0.0313

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0446

EpiControl AF: 0.0470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spastic paraplegia 11 (5)
-	-	4	not specified (4)
-	-	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	-0.26
CADD	Benign	7.1
DANN	Benign	0.76
PhyloP100		0.15
Mutation Taster		=81/19	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: rs36014111; hg19: chr15-44900675;