chr15-44651599-T-C

Variant names:

• chr15-44651599-T-C
• rs3759873
• NM_025137.4:c.1348A>G

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.1348A>G​(p.Ile450Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,166 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (60 hom., cov: 32)
  • Exomes 𝑓: 0.010 (308 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.354
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001638025).
• BP6: Variant 15-44651599-T-C is Benign according to our data. Variant chr15-44651599-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0927 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.1348A>G	p.Ile450Val	missense	Exon 6 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.1348A>G	p.Ile450Val	missense	Exon 6 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.1348A>G	p.Ile450Val	missense	Exon 6 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.1348A>G	p.Ile450Val	missense	Exon 6 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.1348A>G	p.Ile450Val	missense	Exon 6 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.1348A>G	p.Ile450Val	missense	Exon 6 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2226 AN: 152162 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0187 AC: 4695 AN: 251442 AF XY: 0.0188

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.0965

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0103 AC: 15023 AN: 1461886 Hom.: 308 Cov.: 35 AF XY: 0.0110 AC XY: 7996 AN XY: 727244

African (AFR) AF: 0.0158 AC: 529 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 173 AN: 26136

East Asian (EAS) AF: 0.0753 AC: 2989 AN: 39698

South Asian (SAS) AF: 0.0367 AC: 3165 AN: 86258

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

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.00494 AC: 5493 AN: 1112006

Other (OTH) AF: 0.0131 AC: 794 AN: 60396

GnomAD4 genome AF: 0.0147 AC: 2241 AN: 152280 Hom.: 60 Cov.: 32 AF XY: 0.0176 AC XY: 1314 AN XY: 74458

African (AFR) AF: 0.0149 AC: 619 AN: 41564

American (AMR) AF: 0.00353 AC: 54 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.0998 AC: 517 AN: 5182

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4830

European-Finnish (FIN) AF: 0.0354 AC: 375 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 68012

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00710 Hom.: 23

Bravo AF: 0.0129

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.0187 AC: 2273

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hereditary spastic paraplegia 11 (4)
-	-	2	not provided (2)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.3
DANN	Benign	0.27
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.35
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.075
Sift	Benign	0.74	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.033
ClinPred		0.0027	T
GERP RS		1.4
Varity_R		0.012
gMVP		0.16
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: rs3759873; hg19: chr15-44943797; COSMIC: COSV55998743;