rs774774648

Variant names:

• chr16-89526347-C-T
• rs774774648
• NM_003119.4:c.637C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001363850.1(SPG7):​c.637C>T​(p.Arg213*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,936 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: SPG7 NM_001363850.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 2.76
• Publications: 3 publications found

Genes affected

SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

SPG7 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-89526347-C-T is Pathogenic according to our data. Variant chr16-89526347-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 285368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363850.1. 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
	SPG7	NM_003119.4	MANE Select	c.637C>T	p.Arg213*	stop_gained	Exon 5 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.637C>T	p.Arg213*	stop_gained	Exon 5 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.637C>T	p.Arg213*	stop_gained	Exon 5 of 10	NP_955399.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.637C>T	p.Arg213*	stop_gained	Exon 5 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.637C>T	p.Arg213*	stop_gained	Exon 5 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.637C>T	p.Arg213*	stop_gained	Exon 5 of 10	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 20 AN: 251492 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111992

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000475 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary spastic paraplegia 7 (4)
2	-	-	not provided (2)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	SPG7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		2.8
Vest4		0.92
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs774774648; hg19: chr16-89592755;