rs80338868

Variant names:

• chr15-44657156-C-T
• rs80338868
• NM_025137.4:c.808G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-44657156-C-T
• chr15-44657156-C-G

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.808G>A​(p.Val270Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,614,162 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (62 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.12
• Publications: 18 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=0.0037087202).
• BP6: Variant 15-44657156-C-T is Benign according to our data. Variant chr15-44657156-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00804 (1224/152296) while in subpopulation NFE AF = 0.00941 (640/68028). AF 95% confidence interval is 0.0088. There are 6 homozygotes in GnomAd4. There are 549 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.808G>A	p.Val270Ile	missense	Exon 4 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.808G>A	p.Val270Ile	missense	Exon 4 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.808G>A	p.Val270Ile	missense	Exon 4 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.808G>A	p.Val270Ile	missense	Exon 4 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.808G>A	p.Val270Ile	missense	Exon 4 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.808G>A	p.Val270Ile	missense	Exon 4 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152178 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00839

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00608 AC: 1528 AN: 251422 AF XY: 0.00592

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00735

Gnomad NFE exome AF: 0.00826

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00824 AC: 12041 AN: 1461866 Hom.: 62 Cov.: 31 AF XY: 0.00803 AC XY: 5836 AN XY: 727226

African (AFR) AF: 0.00878 AC: 294 AN: 33480

American (AMR) AF: 0.00436 AC: 195 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86258

European-Finnish (FIN) AF: 0.00666 AC: 356 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00950 AC: 10561 AN: 1111994

Other (OTH) AF: 0.00647 AC: 391 AN: 60396

GnomAD4 genome AF: 0.00804 AC: 1224 AN: 152296 Hom.: 6 Cov.: 32 AF XY: 0.00737 AC XY: 549 AN XY: 74476

African (AFR) AF: 0.00871 AC: 362 AN: 41554

American (AMR) AF: 0.00471 AC: 72 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00839 AC: 89 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00941 AC: 640 AN: 68028

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00867 Hom.: 31

Bravo AF: 0.00750

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00978 AC: 43

ESP6500EA AF: 0.0104 AC: 89

ExAC AF: 0.00607 AC: 737

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00867

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Hereditary spastic paraplegia 11 (6)
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.085
Sift	Benign	0.036	D
Sift4G	Benign	0.084	T
Polyphen		0.95	P
Vest4		0.16
MVP		0.32
MPC		0.23
ClinPred		0.036	T
GERP RS		5.7
Varity_R		0.082
gMVP		0.29
Mutation Taster		=98/2	polymorphism

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: rs80338868; hg19: chr15-44949354;