chr15-64963704-G-A

Variant names:

• chr15-64963704-G-A
• rs147428832
• NM_016630.7:c.843C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016630.7(SPG21):​c.843C>T​(p.Tyr281Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,613,974 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.020 (361 hom.)
• Consequence: SPG21 NM_016630.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01
• Publications: 5 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-64963704-G-A is Benign according to our data. Variant chr15-64963704-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (2102/152306) while in subpopulation NFE AF = 0.0224 (1527/68026). AF 95% confidence interval is 0.0215. There are 22 homozygotes in GnomAd4. There are 985 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.843C>T	p.Tyr281Tyr	synonymous	Exon 9 of 9	NP_057714.1	Q9NZD8-1
	SPG21	NM_001127889.5		c.843C>T	p.Tyr281Tyr	synonymous	Exon 9 of 9	NP_001121361.1	Q9NZD8-1
	SPG21	NM_001127890.5		c.762C>T	p.Tyr254Tyr	synonymous	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.843C>T	p.Tyr281Tyr	synonymous	Exon 9 of 9	ENSP00000204566.2	Q9NZD8-1
	SPG21	ENST00000433215.6	TSL:1	c.843C>T	p.Tyr281Tyr	synonymous	Exon 9 of 9	ENSP00000404111.2	Q9NZD8-1
	SPG21	ENST00000854124.1		c.843C>T	p.Tyr281Tyr	synonymous	Exon 9 of 9	ENSP00000524183.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2099 AN: 152188 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0147 AC: 3692 AN: 251416 AF XY: 0.0155

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00627

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00952

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0202 AC: 29534 AN: 1461668 Hom.: 361 Cov.: 32 AF XY: 0.0201 AC XY: 14612 AN XY: 727156

African (AFR) AF: 0.00338 AC: 113 AN: 33476

American (AMR) AF: 0.00626 AC: 280 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00651 AC: 170 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0138 AC: 1187 AN: 86246

European-Finnish (FIN) AF: 0.0129 AC: 687 AN: 53414

Middle Eastern (MID) AF: 0.0300 AC: 172 AN: 5732

European-Non Finnish (NFE) AF: 0.0233 AC: 25891 AN: 1111868

Other (OTH) AF: 0.0171 AC: 1030 AN: 60380

GnomAD4 genome AF: 0.0138 AC: 2102 AN: 152306 Hom.: 22 Cov.: 32 AF XY: 0.0132 AC XY: 985 AN XY: 74480

African (AFR) AF: 0.00418 AC: 174 AN: 41578

American (AMR) AF: 0.0108 AC: 165 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4820

European-Finnish (FIN) AF: 0.00923 AC: 98 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1527 AN: 68026

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0182 Hom.: 15

Bravo AF: 0.0128

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Mast syndrome (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.77
DANN	Benign	0.45
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs147428832; hg19: chr15-65256045; COSMIC: COSV52603939;