rs201918221

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_025137.4(SPG11):c.7161A>T(p.Gln2387His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -1.07

Publications

2 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, 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

SPG11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009516776).

BP6

Variant 15-44563292-T-A is Benign according to our data. Variant chr15-44563292-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448469.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000749 (114/152194) while in subpopulation AFR AF = 0.0027 (112/41428). AF 95% confidence interval is 0.0023. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG11	NM_025137.4	MANE Select	c.7161A>T	p.Gln2387His	missense	Exon 40 of 40	NP_079413.3
SPG11	NM_001411132.1		c.7017A>T	p.Gln2339His	missense	Exon 40 of 40	NP_001398061.1	A0A804HID9
SPG11	NM_001160227.2		c.6822A>T	p.Gln2274His	missense	Exon 38 of 38	NP_001153699.1	Q96JI7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG11	ENST00000261866.12	TSL:1 MANE Select	c.7161A>T	p.Gln2387His	missense	Exon 40 of 40	ENSP00000261866.7	Q96JI7-1
SPG11	ENST00000535302.6	TSL:1	c.6822A>T	p.Gln2274His	missense	Exon 38 of 38	ENSP00000445278.2	Q96JI7-3
SPG11	ENST00000427534.6	TSL:1	c.6764A>T	p.Asn2255Ile	missense	Exon 37 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes

AF:

0.000750

AC:

114

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000239

AC:

AN:

251346

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1460494

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

726686

show subpopulations

African (AFR)

AF:

0.00234

AC:

AN:

33354

American (AMR)

AF:

0.000201

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111030

Other (OTH)

AF:

0.000166

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152194

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00270

AC:

112

AN:

41428

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

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:

0.000149

Hom.:

Bravo

AF:

0.000933

ExAC

AF:

0.000346

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Hereditary spastic paraplegia 11 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Benign

9.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.45

M_CAP

Benign

0.024

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.98

PhyloP100

-1.1

PROVEAN

Benign

-0.42

REVEL

Benign

0.072

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0050

Vest4

0.44

MVP

0.35

ClinPred

0.0087

GERP RS

0.57

Varity_R

0.062

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over