15-64965260-T-G

Variant names:

• chr15-64965260-T-G
• rs72740676
• NM_016630.7:c.810+60A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016630.7(SPG21):​c.810+60A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,607,742 control chromosomes in the GnomAD database, including 321 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 (30 hom., cov: 32)
  • Exomes 𝑓: 0.019 (291 hom.)
• Consequence: SPG21 NM_016630.7 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.980
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 15-64965260-T-G is Benign according to our data. Variant chr15-64965260-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1212151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0167 (2536/152294) while in subpopulation AMR AF = 0.0237 (362/15298). AF 95% confidence interval is 0.0217. There are 30 homozygotes in GnomAd4. There are 1324 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.810+60A>C		intron	N/A	NP_057714.1	Q9NZD8-1
	SPG21	NM_001127889.5		c.810+60A>C		intron	N/A	NP_001121361.1	Q9NZD8-1
	SPG21	NM_001127890.5		c.729+60A>C		intron	N/A	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.810+60A>C		intron	N/A	ENSP00000204566.2	Q9NZD8-1
	SPG21	ENST00000433215.6	TSL:1	c.810+60A>C		intron	N/A	ENSP00000404111.2	Q9NZD8-1
	SPG21	ENST00000854124.1		c.810+60A>C		intron	N/A	ENSP00000524183.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2533 AN: 152176 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0188 AC: 27346 AN: 1455448 Hom.: 291 AF XY: 0.0187 AC XY: 13524 AN XY: 724446

African (AFR) AF: 0.00258 AC: 86 AN: 33346

American (AMR) AF: 0.0145 AC: 649 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 1003 AN: 26082

East Asian (EAS) AF: 0.00232 AC: 92 AN: 39664

South Asian (SAS) AF: 0.00688 AC: 592 AN: 86044

European-Finnish (FIN) AF: 0.0269 AC: 1438 AN: 53368

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5746

European-Non Finnish (NFE) AF: 0.0201 AC: 22290 AN: 1106354

Other (OTH) AF: 0.0186 AC: 1117 AN: 60180

GnomAD4 genome AF: 0.0167 AC: 2536 AN: 152294 Hom.: 30 Cov.: 32 AF XY: 0.0178 AC XY: 1324 AN XY: 74460

African (AFR) AF: 0.00382 AC: 159 AN: 41570

American (AMR) AF: 0.0237 AC: 362 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3470

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5184

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4824

European-Finnish (FIN) AF: 0.0355 AC: 377 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1342 AN: 68022

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0147 Hom.: 3

Bravo AF: 0.0149

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.55
DANN	Benign	0.75
PhyloP100		-0.98
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs72740676; hg19: chr15-65257601;