15-64963727-G-T

Variant names:

• chr15-64963727-G-T
• NM_016630.7:c.820C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016630.7(SPG21):​c.820C>A​(p.Leu274Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SPG21 NM_016630.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21382466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG21	NM_016630.7	c.820C>A	p.Leu274Met	missense_variant	Exon 9 of 9	ENST00000204566.7	NP_057714.1
SPG21	NM_001127889.5	c.820C>A	p.Leu274Met	missense_variant	Exon 9 of 9		NP_001121361.1
SPG21	NM_001127890.5	c.739C>A	p.Leu247Met	missense_variant	Exon 8 of 8		NP_001121362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG21	ENST00000204566.7	c.820C>A	p.Leu274Met	missense_variant	Exon 9 of 9	1	NM_016630.7	ENSP00000204566.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461160 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Sep 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;.
Eigen	Benign	0.052
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N;.;N;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.59	N;N;N;N
REVEL	Benign	0.074
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.086	T;T;T;T
Polyphen		0.014	B;.;B;B
Vest4		0.33
MutPred		0.42		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);.;
MVP		0.27
MPC		0.32
ClinPred		0.55	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-65256068;