rs115661328

Variant names:

• chr16-89530702-G-A
• rs115661328
• NM_003119.4:c.881G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89530702-G-A
• chr16-89530702-G-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_001363850.1(SPG7):​c.881G>A​(p.Arg294His) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,614,072 control chromosomes in the GnomAD database, including 61 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. R294G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: SPG7 NM_001363850.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.39
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00891611).
• BP6: Variant 16-89530702-G-A is Benign according to our data. Variant chr16-89530702-G-A is described in ClinVar as Benign. ClinVar VariationId is 139237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1631/152194) while in subpopulation AFR AF = 0.0377 (1563/41490). AF 95% confidence interval is 0.0361. There are 34 homozygotes in GnomAd4. There are 791 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AD,AR gene

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.881G>A	p.Arg294His	missense	Exon 7 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.881G>A	p.Arg294His	missense	Exon 7 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.881G>A	p.Arg294His	missense	Exon 7 of 10	NP_955399.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.881G>A	p.Arg294His	missense	Exon 7 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.881G>A	p.Arg294His	missense	Exon 7 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.881G>A	p.Arg294His	missense	Exon 7 of 10	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1628 AN: 152076 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00272 AC: 683 AN: 251406 AF XY: 0.00201

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00109 AC: 1596 AN: 1461878 Hom.: 27 Cov.: 47 AF XY: 0.000967 AC XY: 703 AN XY: 727242

African (AFR) AF: 0.0415 AC: 1388 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112010

Other (OTH) AF: 0.00172 AC: 104 AN: 60392

GnomAD4 genome AF: 0.0107 AC: 1631 AN: 152194 Hom.: 34 Cov.: 33 AF XY: 0.0106 AC XY: 791 AN XY: 74434

African (AFR) AF: 0.0377 AC: 1563 AN: 41490

American (AMR) AF: 0.00294 AC: 45 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00406 Hom.: 40

Bravo AF: 0.0118

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00338 AC: 411

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spastic paraplegia 7 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.26
Sift	Benign	0.20	T
Sift4G	Benign	0.082	T
Polyphen		0.97	D
Vest4		0.57
MVP		0.78
MPC		0.82
ClinPred		0.026	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.68
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115661328; hg19: chr16-89597110;