rs149251662

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016630.7(SPG21):c.538G>A(p.Ala180Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

SPG21
NM_016630.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.88

Publications

8 publications found

Variant links:

Genes affected

SPG21 (HGNC:20373): (SPG21 abhydrolase domain containing, maspardin) The protein encoded by this gene binds to the hydrophobic C-terminal amino acids of CD4 which are involved in repression of T cell activation. The interaction with CD4 is mediated by the noncatalytic alpha/beta hydrolase fold domain of this protein. It is thus proposed that this gene product modulates the stimulatory activity of CD4. Mutations in this gene are associated with autosomal recessive spastic paraplegia 21 (SPG21), also known as mast syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

SPG21 Gene-Disease associations (from GenCC):

mast syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SPG21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03689331).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016630.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG21	NM_016630.7	MANE Select	c.538G>A	p.Ala180Thr	missense	Exon 6 of 9	NP_057714.1	Q9NZD8-1
SPG21	NM_001127889.5		c.538G>A	p.Ala180Thr	missense	Exon 6 of 9	NP_001121361.1	Q9NZD8-1
SPG21	NM_001127890.5		c.457G>A	p.Ala153Thr	missense	Exon 5 of 8	NP_001121362.1	Q9NZD8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG21	ENST00000204566.7	TSL:1 MANE Select	c.538G>A	p.Ala180Thr	missense	Exon 6 of 9	ENSP00000204566.2	Q9NZD8-1
SPG21	ENST00000433215.6	TSL:1	c.538G>A	p.Ala180Thr	missense	Exon 6 of 9	ENSP00000404111.2	Q9NZD8-1
SPG21	ENST00000854124.1		c.538G>A	p.Ala180Thr	missense	Exon 6 of 9	ENSP00000524183.1

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000943

AC:

237

AN:

251316

AF XY:

0.000854

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00150

AC:

2187

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1049

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.00139

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000174

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000450

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00179

AC:

1990

AN:

1111928

Other (OTH)

AF:

0.00142

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.00115

AC:

175

AN:

152326

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41578

American (AMR)

AF:

0.00255

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00165

AC:

112

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00145

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.000964

AC:

117

EpiCase

AF:

0.00180

EpiControl

AF:

0.00219

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Mast syndrome (2)

Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.030

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.2

PhyloP100

7.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.5

REVEL

Benign

0.12

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.037

Polyphen

0.036

Vest4

0.31

MVP

0.77

MPC

0.89

ClinPred

0.052

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.67

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over