16-89508419-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_003119.4(SPG7):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,336,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SPG7 NM_003119.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.83

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003119.4 (SPG7) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1070427
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89508419-T-G is Pathogenic according to our data. Variant chr16-89508419-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2627663.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.2T>G	p.Met1?	start_lost	1/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.2T>G	p.Met1?	start_lost	1/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1336898 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 659250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.45e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.071	T;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	0.96	D;D
Polyphen		0.93	P;.;.;.;.;.;.;.;.;D
Vest4		0.69, 0.70
MutPred		0.78		Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);Gain of methylation at M1 (P = 0.0095);
MVP		0.97
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		0.66

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: rs1332265538; hg19: chr16-89574827;