15-44572707-C-T

Variant names:

• chr15-44572707-C-T
• rs115970214
• NM_025137.4:c.6319G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025137.4(SPG11):​c.6319G>A​(p.Val2107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,082 control chromosomes in the GnomAD database, including 33 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (16 hom., cov: 31)
  • Exomes 𝑓: 0.00084 (17 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.57
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007181555).
• BP6: Variant 15-44572707-C-T is Benign according to our data. Variant chr15-44572707-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00879 (1338/152202) while in subpopulation AFR AF = 0.0309 (1281/41518). AF 95% confidence interval is 0.0294. There are 16 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.6319G>A	p.Val2107Ile	missense	Exon 33 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6175G>A	p.Val2059Ile	missense	Exon 33 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.5980G>A	p.Val1994Ile	missense	Exon 31 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.6319G>A	p.Val2107Ile	missense	Exon 33 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.5980G>A	p.Val1994Ile	missense	Exon 31 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.6319G>A	p.Val2107Ile	missense	Exon 33 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1340 AN: 152084 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00228 AC: 573 AN: 251474 AF XY: 0.00165

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000844 AC: 1234 AN: 1461880 Hom.: 17 Cov.: 32 AF XY: 0.000729 AC XY: 530 AN XY: 727242

African (AFR) AF: 0.0297 AC: 995 AN: 33480

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1112002

Other (OTH) AF: 0.00179 AC: 108 AN: 60394

GnomAD4 genome AF: 0.00879 AC: 1338 AN: 152202 Hom.: 16 Cov.: 31 AF XY: 0.00829 AC XY: 617 AN XY: 74414

African (AFR) AF: 0.0309 AC: 1281 AN: 41518

American (AMR) AF: 0.00281 AC: 43 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00338 Hom.: 8

Bravo AF: 0.00965

ESP6500AA AF: 0.0278 AC: 122

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spastic paraplegia 11 (5)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.28
Sift	Benign	0.059	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.15
MVP		0.68
MPC		0.22
ClinPred		0.035	T
GERP RS		5.7
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.076
gMVP		0.16
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs115970214; hg19: chr15-44864905; COSMIC: COSV99968702; COSMIC: COSV99968702;