rs760497590

Variant names:

• chr15-64980866-C-A
• rs760497590
• NM_016630.7:c.223G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 17/24 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A75T) has been classified as Uncertain significance.

• 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
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2304106).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG21	NM_016630.7	MANE Select	c.223G>T	p.Ala75Ser	missense splice_region	Exon 3 of 9	NP_057714.1	Q9NZD8-1
	SPG21	NM_001127889.5		c.223G>T	p.Ala75Ser	missense splice_region	Exon 3 of 9	NP_001121361.1	Q9NZD8-1
	SPG21	NM_001127890.5		c.223G>T	p.Ala75Ser	missense splice_region	Exon 3 of 8	NP_001121362.1	Q9NZD8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG21	ENST00000204566.7	TSL:1 MANE Select	c.223G>T	p.Ala75Ser	missense splice_region	Exon 3 of 9	ENSP00000204566.2	Q9NZD8-1
	SPG21	ENST00000433215.6	TSL:1	c.223G>T	p.Ala75Ser	missense splice_region	Exon 3 of 9	ENSP00000404111.2	Q9NZD8-1
	SPG21	ENST00000854124.1		c.223G>T	p.Ala75Ser	missense splice_region	Exon 3 of 9	ENSP00000524183.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.23
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		4.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.46
MutPred		0.56		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

Other links and lift over

dbSNP: rs760497590; hg19: chr15-65273204;