15-44651559-A-G

Variant names:

• chr15-44651559-A-G
• rs3759871
• NM_025137.4:c.1388T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025137.4(SPG11):​c.1388T>C​(p.Phe463Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,660 control chromosomes in the GnomAD database, including 167,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17741 hom., cov: 32)
  • Exomes 𝑓: 0.45 (150009 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.39
• Publications: 51 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Illumina
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.9492717E-4).
• BP6: Variant 15-44651559-A-G is Benign according to our data. Variant chr15-44651559-A-G is described in ClinVar as Benign. ClinVar VariationId is 41271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.534 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.1388T>C	p.Phe463Ser	missense	Exon 6 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.1388T>C	p.Phe463Ser	missense	Exon 6 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.1388T>C	p.Phe463Ser	missense	Exon 6 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.1388T>C	p.Phe463Ser	missense	Exon 6 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.1388T>C	p.Phe463Ser	missense	Exon 6 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.1388T>C	p.Phe463Ser	missense	Exon 6 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73026 AN: 151916 Hom.: 17722 Cov.: 32

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.468 AC: 117565 AN: 251374 AF XY: 0.458

Gnomad AFR exome AF: 0.528

Gnomad AMR exome AF: 0.568

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.456

Gnomad FIN exome AF: 0.482

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.451 AC: 659493 AN: 1461626 Hom.: 150009 Cov.: 52 AF XY: 0.449 AC XY: 326424 AN XY: 727136

African (AFR) AF: 0.524 AC: 17536 AN: 33472

American (AMR) AF: 0.569 AC: 25437 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12131 AN: 26134

East Asian (EAS) AF: 0.541 AC: 21486 AN: 39696

South Asian (SAS) AF: 0.368 AC: 31704 AN: 86252

European-Finnish (FIN) AF: 0.492 AC: 26287 AN: 53416

Middle Eastern (MID) AF: 0.360 AC: 2076 AN: 5768

European-Non Finnish (NFE) AF: 0.446 AC: 495687 AN: 1111784

Other (OTH) AF: 0.450 AC: 27149 AN: 60380

GnomAD4 genome AF: 0.481 AC: 73084 AN: 152034 Hom.: 17741 Cov.: 32 AF XY: 0.480 AC XY: 35695 AN XY: 74320

African (AFR) AF: 0.523 AC: 21682 AN: 41442

American (AMR) AF: 0.543 AC: 8298 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1613 AN: 3470

East Asian (EAS) AF: 0.482 AC: 2498 AN: 5184

South Asian (SAS) AF: 0.367 AC: 1766 AN: 4812

European-Finnish (FIN) AF: 0.481 AC: 5078 AN: 10554

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30473 AN: 67984

Other (OTH) AF: 0.473 AC: 1000 AN: 2112

Alfa AF: 0.459 Hom.: 74625

Bravo AF: 0.490

TwinsUK AF: 0.437 AC: 1622

ALSPAC AF: 0.435 AC: 1678

ESP6500AA AF: 0.525 AC: 2310

ESP6500EA AF: 0.456 AC: 3917

ExAC AF: 0.466 AC: 56539

Asia WGS AF: 0.462 AC: 1607 AN: 3478

EpiCase AF: 0.445

EpiControl AF: 0.454

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Hereditary spastic paraplegia 11 (7)
-	-	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
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.00049	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Polyphen		0.021	B
Vest4		0.20
MPC		0.30
ClinPred		0.016	T
GERP RS		4.9
Varity_R		0.096
gMVP		0.40
Mutation Taster		=99/1	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: rs3759871; hg19: chr15-44943757; COSMIC: COSV55992310;