NM_025137.4:c.2621-8dupT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_025137.4(SPG11):c.2621-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,582,566 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 3 hom. )

Consequence

SPG11
NM_025137.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.681

Publications

0 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: 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

SPG11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 15-44620410-G-GA is Benign according to our data. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44620410-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 413993.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 = 0.00358 (542/151388) while in subpopulation AFR AF = 0.0122 (503/41296). AF 95% confidence interval is 0.0113. There are 4 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.2621-8dupT		splice_region_variant, intron_variant	Intron 14 of 39	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 link	c.2621-8dupT		splice_region_variant, intron_variant	Intron 14 of 39	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00359

AC:

543

AN:

151274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00110

AC:

259

AN:

234770

AF XY:

0.000894

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.00117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00146

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000938

Gnomad OTH exome

AF:

0.000354

GnomAD4 exome

AF:

0.000419

AC:

600

AN:

1431178

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

275

AN XY:

713172

show subpopulations

African (AFR)

AF:

0.0116

AC:

374

AN:

32104

American (AMR)

AF:

0.00109

AC:

AN:

42276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25614

East Asian (EAS)

AF:

0.000559

AC:

AN:

39326

South Asian (SAS)

AF:

0.0000477

AC:

AN:

83892

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.000530

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0000862

AC:

AN:

1090060

Other (OTH)

AF:

0.000947

AC:

AN:

59112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00358

AC:

542

AN:

151388

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

254

AN XY:

73920

show subpopulations

African (AFR)

AF:

0.0122

AC:

503

AN:

41296

American (AMR)

AF:

0.00191

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000969

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000590

AC:

AN:

67806

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.00408

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 28, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG11: BP4, BS1, BS2 -

Hereditary spastic paraplegia 11

Benign:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SPG11-related disorder

Benign:1

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Apr 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 5

Benign:1

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X

Benign:1

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.68

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over