rs116319889

Positions:

chr16-89531948-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_003119.4(SPG7):c.1032C>T(p.Gly344=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,614,118 control chromosomes in the GnomAD database, including 56 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 0.0045 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 51 hom. )

Consequence

SPG7
NM_003119.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -1.58

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 16-89531948-C-T is Benign according to our data. Variant chr16-89531948-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139239.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr16-89531948-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.58 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00453 (690/152352) while in subpopulation NFE AF= 0.00725 (493/68026). AF 95% confidence interval is 0.00672. There are 5 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4 linkuse as main transcript	c.1032C>T	p.Gly344=	synonymous_variant	8/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 linkuse as main transcript	c.1032C>T	p.Gly344=	synonymous_variant	8/17		NM_003119.4	ENSP00000495795	P2	Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

693

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00494

AC:

1240

AN:

250820

Hom.:

AF XY:

0.00531

AC XY:

721

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00598

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00775

Gnomad OTH exome

AF:

0.00605

GnomAD4 exome

AF:

0.00591

AC:

8645

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00606

AC XY:

4410

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00266

Gnomad4 ASJ exome

AF:

0.00356

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00627

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.00656

Gnomad4 OTH exome

AF:

0.00671

GnomAD4 genome

AF:

0.00453

AC:

690

AN:

152352

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

299

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00725

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00610

Hom.:

Bravo

AF:

0.00491

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00796

EpiControl

AF:

0.00871

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 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	Athena Diagnostics	Jul 15, 2020	- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 08, 2020

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

SPG7: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.67

DANN

Benign

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over