chr15-44610839-C-A

Variant names:

Variant summary

Our verdict is . The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025137.4(SPG11):c.3291+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000274 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPG11
NM_025137.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 6.68

Publications

5 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Genomics England PanelApp, ClinGen
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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
juvenile amyotrophic lateral sclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SPG11 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_025137.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-44610839-C-A is Pathogenic according to our data. Variant chr15-44610839-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 41304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPG11	NM_025137.4	MANE Select	c.3291+1G>T	splice_donor intron	N/A	NP_079413.3
SPG11	NM_001411132.1		c.3291+1G>T	splice_donor intron	N/A	NP_001398061.1	A0A804HID9
SPG11	NM_001160227.2		c.3291+1G>T	splice_donor intron	N/A	NP_001153699.1	Q96JI7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPG11	ENST00000261866.12	TSL:1 MANE Select	c.3291+1G>T	splice_donor intron	N/A	ENSP00000261866.7	Q96JI7-1
SPG11	ENST00000535302.6	TSL:1	c.3291+1G>T	splice_donor intron	N/A	ENSP00000445278.2	Q96JI7-3
SPG11	ENST00000427534.6	TSL:1	c.3291+1G>T	splice_donor intron	N/A	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111822

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 11 (3)

Charcot-Marie-Tooth disease axonal type 2X (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over