rs61747711

Positions:

• chr16-89556997-C-T

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.2292C>T​(p.Ile764=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,613,830 control chromosomes in the GnomAD database, including 1,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (93 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1184 hom.)
• Consequence: SPG7 NM_003119.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.20

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=-0.77).
• BP6: Variant 16-89556997-C-T is Benign according to our data. Variant chr16-89556997-C-T is described in ClinVar as [Benign]. Clinvar id is 139250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89556997-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0281 (4274/152306) while in subpopulation NFE AF= 0.0409 (2781/68014). AF 95% confidence interval is 0.0396. There are 93 homozygotes in gnomad4. There are 1970 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 93 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.2292C>T	p.Ile764=	synonymous_variant	17/17	ENST00000645818.2	NP_003110.1
SPG7	XM_047434540.1	c.978C>T	p.Ile326=	synonymous_variant	9/9		XP_047290496.1
SPG7	NM_001363850.1	c.*70C>T		3_prime_UTR_variant	18/18		NP_001350779.1
SPG7	XM_047434537.1	c.*70C>T		3_prime_UTR_variant	13/13		XP_047290493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.2292C>T	p.Ile764=	synonymous_variant	17/17		NM_003119.4	ENSP00000495795	P2

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4276 AN: 152188 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0406

GnomAD3 exomes AF: 0.0287 AC: 7212 AN: 251238 Hom.: 144 AF XY: 0.0292 AC XY: 3971 AN XY: 135866

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00843

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0378 AC: 55173 AN: 1461524 Hom.: 1184 Cov.: 31 AF XY: 0.0368 AC XY: 26774 AN XY: 727048

Gnomad4 AFR exome AF: 0.00932

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00883

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0433

Gnomad4 OTH exome AF: 0.0369

GnomAD4 genome AF: 0.0281 AC: 4274 AN: 152306 Hom.: 93 Cov.: 32 AF XY: 0.0265 AC XY: 1970 AN XY: 74472

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0798

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0409

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0390 Hom.: 148

Bravo AF: 0.0289

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0450

EpiControl AF: 0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2012	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 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.043
DANN	Benign	0.87
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: rs61747711; hg19: chr16-89623405;