rs535030441

Positions:

• chr16-89508421-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_003119.4(SPG7):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,490,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 1.39

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034443736).
• BP6: Variant 16-89508421-G-A is Benign according to our data. Variant chr16-89508421-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215198.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.4G>A	p.Ala2Thr	missense_variant	1/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.4G>A	p.Ala2Thr	missense_variant	1/17		NM_003119.4	ENSP00000495795	P2

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000691

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000731 AC: 66 AN: 90242 Hom.: 0 AF XY: 0.000627 AC XY: 32 AN XY: 51012

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000584

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.000739 AC: 989 AN: 1338014 Hom.: 0 Cov.: 31 AF XY: 0.000714 AC XY: 471 AN XY: 659790

Gnomad4 AFR exome AF: 0.00315

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.0000423

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000267

Gnomad4 FIN exome AF: 0.000180

Gnomad4 NFE exome AF: 0.000740

Gnomad4 OTH exome AF: 0.000935

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74420

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00157

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000221 AC: 5

Asia WGS AF: 0.000580 AC: 2 AN: 3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. The variant is located in a region that is considered important for protein function and/or structure. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	This variant is associated with the following publications: (PMID: 16534102, 20301286) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 12, 2021	- -

Hereditary spastic paraplegia 7 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;.;.;.;.;.;.;.;.;.
Eigen	Benign	0.071
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.49	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;.;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.69	.;.;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D
Polyphen		0.89	P;.;.;.;.;.;.;.;.;D
Vest4		0.28, 0.29
MVP		0.88
MPC		0.20
ClinPred		0.16	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.61

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: rs535030441; hg19: chr16-89574829;