Genetic Variant SPG21:c.*33G>T (chr15-64963587-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016630.7(SPG21):c.*33G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,554,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SPG21
NM_016630.7 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.398

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

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	Effect	Exon Rank	Protein	UniProt
SPG21	NM_016630.7	MANE Select	c.*33G>T	3_prime_UTR	Exon 9 of 9	NP_057714.1	Q9NZD8-1
SPG21	NM_001127889.5		c.*33G>T	3_prime_UTR	Exon 9 of 9	NP_001121361.1	Q9NZD8-1
SPG21	NM_001127890.5		c.*33G>T	3_prime_UTR	Exon 8 of 8	NP_001121362.1	Q9NZD8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPG21	ENST00000204566.7	TSL:1 MANE Select	c.*33G>T	3_prime_UTR	Exon 9 of 9	ENSP00000204566.2	Q9NZD8-1
SPG21	ENST00000433215.6	TSL:1	c.*33G>T	3_prime_UTR	Exon 9 of 9	ENSP00000404111.2	Q9NZD8-1
SPG21	ENST00000854124.1		c.*33G>T	3_prime_UTR	Exon 9 of 9	ENSP00000524183.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251076

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000285

AC:

AN:

1401984

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32304

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

85054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4650

European-Non Finnish (NFE)

AF:

0.00000378

AC:

AN:

1058784

Other (OTH)

AF:

0.00

AC:

AN:

58248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.7

(source)

DANN

Benign

0.78

PhyloP100

-0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over