rs12960

Variant names:

• chr16-89553920-G-A
• rs12960
• NM_003119.4:c.2063G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_001363850.1(SPG7):​c.2063G>A​(p.Arg688Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,612,442 control chromosomes in the GnomAD database, including 26,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R688W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.13 (1644 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24507 hom.)
• Consequence: SPG7 NM_001363850.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.61
• Publications: 66 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: Benign. The variant received -16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001363850.1
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89553919-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1380458.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019080639).
• BP6: Variant 16-89553920-G-A is Benign according to our data. Variant chr16-89553920-G-A is described in ClinVar as Benign. ClinVar VariationId is 130370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

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.2063G>A	p.Arg688Gln	missense	Exon 15 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.2063G>A	p.Arg688Gln	missense	Exon 15 of 18	NP_001350779.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.2063G>A	p.Arg688Gln	missense	Exon 15 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.2042G>A	p.Arg681Gln	missense	Exon 15 of 17	ENSP00000268704.3
	SPG7	ENST00000918773.1		c.2153G>A	p.Arg718Gln	missense	Exon 15 of 17	ENSP00000588832.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19841 AN: 152172 Hom.: 1646 Cov.: 33

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.148 AC: 36840 AN: 249596 AF XY: 0.152

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.0887

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.0892

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.178 AC: 260547 AN: 1460152 Hom.: 24507 Cov.: 33 AF XY: 0.178 AC XY: 129313 AN XY: 726386

African (AFR) AF: 0.0284 AC: 949 AN: 33458

American (AMR) AF: 0.0929 AC: 4153 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5720 AN: 26128

East Asian (EAS) AF: 0.127 AC: 5024 AN: 39698

South Asian (SAS) AF: 0.143 AC: 12368 AN: 86230

European-Finnish (FIN) AF: 0.0951 AC: 4977 AN: 52350

Middle Eastern (MID) AF: 0.180 AC: 971 AN: 5394

European-Non Finnish (NFE) AF: 0.194 AC: 215748 AN: 1111832

Other (OTH) AF: 0.176 AC: 10637 AN: 60338

GnomAD4 genome AF: 0.130 AC: 19833 AN: 152290 Hom.: 1644 Cov.: 33 AF XY: 0.126 AC XY: 9360 AN XY: 74464

African (AFR) AF: 0.0354 AC: 1473 AN: 41586

American (AMR) AF: 0.120 AC: 1840 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 821 AN: 3472

East Asian (EAS) AF: 0.145 AC: 748 AN: 5176

South Asian (SAS) AF: 0.146 AC: 703 AN: 4828

European-Finnish (FIN) AF: 0.0852 AC: 904 AN: 10616

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12663 AN: 67990

Other (OTH) AF: 0.163 AC: 345 AN: 2114

Alfa AF: 0.174 Hom.: 4995

Bravo AF: 0.128

TwinsUK AF: 0.198 AC: 733

ALSPAC AF: 0.203 AC: 784

ESP6500AA AF: 0.0375 AC: 165

ESP6500EA AF: 0.194 AC: 1667

ExAC AF: 0.149 AC: 18099

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.198

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary spastic paraplegia 7 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		9.6
PrimateAI	Benign	0.47	T
REVEL	Uncertain	0.39
Polyphen		0.82	P
MPC		0.28
ClinPred		0.041	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.68
Mutation Taster		=53/47	polymorphism (auto)

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: rs12960; hg19: chr16-89620328; COSMIC: COSV51951139; COSMIC: COSV51951139;