rs187330648

Variant names:

• chr16-89508537-G-A
• rs187330648
• NM_003119.4:c.120G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89508537-G-A
• chr16-89508537-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003119.4(SPG7):​c.120G>A​(p.Gly40Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,512,498 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0094 (12 hom., cov: 33)
  • Exomes 𝑓: 0.013 (126 hom.)
• Consequence: SPG7 NM_003119.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7
• Conservation: PhyloP100: 1.29

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]

LOC101927863 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 16-89508537-G-A is Benign according to our data. Variant chr16-89508537-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139253.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, Benign=7, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00936 (1426/152290) while in subpopulation NFE AF= 0.0146 (992/67992). AF 95% confidence interval is 0.0138. There are 12 homozygotes in gnomad4. There are 644 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.120G>A	p.Gly40Gly	synonymous_variant	Exon 1 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.120G>A	p.Gly40Gly	synonymous_variant	Exon 1 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1426 AN: 152182 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00974 AC: 1044 AN: 107214 Hom.: 13 AF XY: 0.00969 AC XY: 580 AN XY: 59846

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.00909

Gnomad EAS exome AF: 0.000279

Gnomad SAS exome AF: 0.00667

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.00947

GnomAD4 exome AF: 0.0127 AC: 17289 AN: 1360208 Hom.: 126 Cov.: 31 AF XY: 0.0125 AC XY: 8400 AN XY: 670778

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00888

Gnomad4 ASJ exome AF: 0.00884

Gnomad4 EAS exome AF: 0.0000613

Gnomad4 SAS exome AF: 0.00671

Gnomad4 FIN exome AF: 0.00338

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00936 AC: 1426 AN: 152290 Hom.: 12 Cov.: 33 AF XY: 0.00865 AC XY: 644 AN XY: 74460

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00509 Hom.: 3

Bravo AF: 0.0106

Asia WGS AF: 0.00116 AC: 4 AN: 3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:1 Uncertain:1 Benign:2

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Feb 16, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Oct 30, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPG7: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.9
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs187330648; hg19: chr16-89574945;