rs11559075

Positions:

• chr16-89556985-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003119.4(SPG7):​c.2280G>A​(p.Pro760=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,613,870 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.013 (144 hom.)
• Consequence: SPG7 NM_003119.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.03

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-89556985-G-A is Benign according to our data. Variant chr16-89556985-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89556985-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0104 (1579/152306) while in subpopulation EAS AF= 0.0178 (92/5176). AF 95% confidence interval is 0.0148. There are 14 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.2280G>A	p.Pro760=	synonymous_variant	17/17	ENST00000645818.2
SPG7	XM_047434540.1	c.966G>A	p.Pro322=	synonymous_variant	9/9
SPG7	NM_001363850.1	c.*58G>A		3_prime_UTR_variant	18/18
SPG7	XM_047434537.1	c.*58G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.2280G>A	p.Pro760=	synonymous_variant	17/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1577 AN: 152188 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.0126 AC: 3159 AN: 251310 Hom.: 20 AF XY: 0.0118 AC XY: 1606 AN XY: 135874

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.0178

Gnomad SAS exome AF: 0.00657

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0133 AC: 19375 AN: 1461564 Hom.: 144 Cov.: 31 AF XY: 0.0130 AC XY: 9456 AN XY: 727082

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.0209

Gnomad4 SAS exome AF: 0.00684

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0104 AC: 1579 AN: 152306 Hom.: 14 Cov.: 32 AF XY: 0.00998 AC XY: 743 AN XY: 74486

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.0129 Hom.: 15

Bravo AF: 0.00910

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.45
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11559075; hg19: chr16-89623393;