15-64974732-C-T

Position:

• chr15-64974732-C-T

Variant summary

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

The NM_016630.7(SPG21):​c.322G>A​(p.Ala108Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SPG21 NM_016630.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG21	NM_016630.7	c.322G>A	p.Ala108Thr	missense_variant	5/9	ENST00000204566.7	NP_057714.1
SPG21	NM_001127889.5	c.322G>A	p.Ala108Thr	missense_variant	5/9		NP_001121361.1
SPG21	NM_001127890.5	c.241G>A	p.Ala81Thr	missense_variant	4/8		NP_001121362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG21	ENST00000204566.7	c.322G>A	p.Ala108Thr	missense_variant	5/9	1	NM_016630.7	ENSP00000204566	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251322 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;T;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.83	N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.63	T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;.;.
Polyphen		0.50	P;P;P;.;.
Vest4		0.93
MutPred		0.62		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.64
MPC		0.53
ClinPred		0.40	T
GERP RS		6.2
Varity_R		0.23
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs587777315; hg19: chr15-65267070;