rs794726906

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-89508418-A-C
• chr16-89508418-A-G
• chr16-89508418-A-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_003119.4(SPG7):​c.1A>C​(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 0.00000599 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: 0.0000060 (0 hom.)
• Consequence: SPG7 NM_003119.4 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.65
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal dominant optic atrophy

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000261118 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 14 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 [Likely_pathogenic] in ClinVar
• PP5: Variant 16-89508418-A-C is Pathogenic according to our data. Variant chr16-89508418-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3236318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 18	NP_001350779.1	A0A2R8Y3M4
	SPG7	NM_199367.3		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 17	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 17	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000341316.6	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000338 AC: 3 AN: 88730 AF XY: 0.0000398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000378

GnomAD4 exome AF: 0.00000599 AC: 8 AN: 1335614 Hom.: 0 Cov.: 31 AF XY: 0.00000607 AC XY: 4 AN XY: 658600

African (AFR) AF: 0.00 AC: 0 AN: 26910

American (AMR) AF: 0.0000667 AC: 2 AN: 29986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23568

East Asian (EAS) AF: 0.00 AC: 0 AN: 30024

South Asian (SAS) AF: 0.00 AC: 0 AN: 74624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1057686

Other (OTH) AF: 0.0000541 AC: 3 AN: 55494

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000471 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary spastic paraplegia 7 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.58
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.72	D
PhyloP100		1.7
PROVEAN	Benign	0.32	N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.52	P
Vest4		0.63
MutPred		0.91		Gain of stability (P = 0.2061)
MVP		0.88
ClinPred		0.98	D
GERP RS		2.8
PromoterAI		-0.78	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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

Other links and lift over

dbSNP: rs794726906; hg19: chr16-89574826;