rs760497590

Positions:

• chr15-64980866-C-A
• chr15-64980866-C-T

Variant summary

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

The NM_016630.7(SPG21):​c.223G>T​(p.Ala75Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPG21 NM_016630.7 missense, splice_region
• Scores: Splicing: ADA: 0.008352
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24

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 (HGNC:):

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=0.2304106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG21	NM_016630.7	c.223G>T	p.Ala75Ser	missense_variant, splice_region_variant	3/9	ENST00000204566.7	NP_057714.1
SPG21	NM_001127889.5	c.223G>T	p.Ala75Ser	missense_variant, splice_region_variant	3/9		NP_001121361.1
SPG21	NM_001127890.5	c.223G>T	p.Ala75Ser	missense_variant, splice_region_variant	3/8		NP_001121362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG21	ENST00000204566.7	c.223G>T	p.Ala75Ser	missense_variant, splice_region_variant	3/9	1	NM_016630.7	ENSP00000204566.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.55
DEOGEN2	Benign	0.16	T;T;.;.;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	.;D;T;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N;N;N;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.56	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;.;.;.
Polyphen		0.0010	B;B;B;.;.;.
Vest4		0.46
MutPred		0.56		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.63
MPC		0.34
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.18
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0084
dbscSNV1_RF	Benign	0.16
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

LitVar

Other links and lift over

dbSNP: rs760497590; hg19: chr15-65273204;