15-64963131-G-A

Position:

• chr15-64963131-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000204566.7(SPG21):​c.*489C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 153,384 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 33)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: SPG21 ENST00000204566.7 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.77

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-64963131-G-A is Benign according to our data. Variant chr15-64963131-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 884249.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0166 (2533/152234) while in subpopulation AMR AF= 0.0236 (361/15290). AF 95% confidence interval is 0.0216. There are 29 homozygotes in gnomad4. There are 1320 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG21	NM_016630.7	c.*489C>T		3_prime_UTR_variant	9/9	ENST00000204566.7	NP_057714.1
SPG21	NM_001127889.5	c.*489C>T		3_prime_UTR_variant	9/9		NP_001121361.1
SPG21	NM_001127890.5	c.*489C>T		3_prime_UTR_variant	8/8		NP_001121362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG21	ENST00000204566.7	c.*489C>T		3_prime_UTR_variant	9/9	1	NM_016630.7	ENSP00000204566	P1
SPG21	ENST00000433215.6	c.*489C>T		3_prime_UTR_variant	9/9	1		ENSP00000404111	P1
SPG21	ENST00000559199.5	c.*489C>T		3_prime_UTR_variant	7/7	2		ENSP00000456365
SPG21	ENST00000561078.5	c.*880C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	5		ENSP00000452865

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2530 AN: 152116 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0209 AC: 24 AN: 1150 Hom.: 0 Cov.: 0 AF XY: 0.0217 AC XY: 14 AN XY: 646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0278

Gnomad4 FIN exome AF: 0.0372

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0166 AC: 2533 AN: 152234 Hom.: 29 Cov.: 33 AF XY: 0.0177 AC XY: 1320 AN XY: 74424

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.00675

Gnomad4 SAS AF: 0.00869

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0164 Hom.: 4

Bravo AF: 0.0149

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mast syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.1
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72740671; hg19: chr15-65255472;