16-89508424-G-GTGC

Position:

• chr16-89508424-G-GTGC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_003119.4(SPG7):​c.21_23dupGCT​(p.Leu8dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,490,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SPG7 NM_003119.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.17

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003119.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.21_23dupGCT	p.Leu8dup	disruptive_inframe_insertion	1/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.21_23dupGCT	p.Leu8dup	disruptive_inframe_insertion	1/17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152068 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000306 AC: 27 AN: 88182 Hom.: 0 AF XY: 0.000280 AC XY: 14 AN XY: 50042

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000280

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000364 AC: 487 AN: 1338536 Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 214 AN XY: 660076

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.000328

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000660

Gnomad4 SAS exome AF: 0.000147

Gnomad4 FIN exome AF: 0.0000299

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.000395

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.000659 AC XY: 49 AN XY: 74408

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00190

Bravo AF: 0.000899

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SPG7: PM4:Supporting -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2024	Identified in a single individual with spastic paraplegia in whom a second variant in the SPG7 gene was not identified (PMID: 21623769); In-frame duplication of 1 amino acid in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 21623769) -

Optic atrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 29, 2020

- -

Hereditary spastic paraplegia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This variant, c.21_23dup, results in the insertion of 1 amino acid(s) of the SPG7 protein (p.Leu8dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs781285980, gnomAD 0.2%). This variant has been observed in individual(s) with spastic paraplegia (PMID: 21623769). ClinVar contains an entry for this variant (Variation ID: 580781). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781285980; hg19: chr16-89574832;