NM_016630.7:c.814C>A

Variant names:

• chr15-64963733-G-T
• rs371953772
• NM_016630.7:c.814C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016630.7(SPG21):​c.814C>A​(p.His272Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SPG21 NM_016630.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

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.814C>A	p.His272Asn	missense	Exon 9 of 9	NP_057714.1	Q9NZD8-1
	SPG21	NM_001127889.5		c.814C>A	p.His272Asn	missense	Exon 9 of 9	NP_001121361.1	Q9NZD8-1
	SPG21	NM_001127890.5		c.733C>A	p.His245Asn	missense	Exon 8 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.814C>A	p.His272Asn	missense	Exon 9 of 9	ENSP00000204566.2	Q9NZD8-1
	SPG21	ENST00000433215.6	TSL:1	c.814C>A	p.His272Asn	missense	Exon 9 of 9	ENSP00000404111.2	Q9NZD8-1
	SPG21	ENST00000854124.1		c.814C>A	p.His272Asn	missense	Exon 9 of 9	ENSP00000524183.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460674 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726750

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0098	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.90	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.85		Gain of helix (P = 0.0854)
MVP		0.43
MPC		1.1
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.67
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs371953772; hg19: chr15-65256074;