16-89508418-A-T

Variant names:

• chr16-89508418-A-T
• rs794726906
• NM_003119.4:c.1A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PS1_Moderate PM2 PP5_Moderate

The NM_003119.4(SPG7):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,335,614 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SPG7 NM_003119.4 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.65

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]

LOC101927863 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 89508547. Lost 0.054 part of the original CDS.
• PS1: Another start lost variant in NM_003119.4 (SPG7) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89508418-A-T is Pathogenic according to our data. Variant chr16-89508418-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3242475.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000113 AC: 1 AN: 88730 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1335614 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 658600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:1

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.58
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.059	T;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
PROVEAN	Benign	0.32	.;.;.;N;.;.;.;.;N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	.;.;.;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D
Polyphen		0.52	P;.;.;.;.;.;.;.;.;P
Vest4		0.63, 0.61
MutPred		0.91		Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);
MVP		0.88
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.93
gMVP		0.37

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: rs794726906; hg19: chr16-89574826;