16-89508422-C-T

Variant names:

• chr16-89508422-C-T
• rs973170664
• NM_003119.4:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003119.4(SPG7):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,490,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.607
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.5C>T	p.Ala2Val	missense	Exon 1 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 18	NP_001350779.1	A0A2R8Y3M4
	SPG7	NM_199367.3		c.5C>T	p.Ala2Val	missense	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.5C>T	p.Ala2Val	missense	Exon 1 of 17	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 1 of 17	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000341316.6	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 1 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1338070 Hom.: 0 Cov.: 31 AF XY: 0.00000455 AC XY: 3 AN XY: 659848

African (AFR) AF: 0.00 AC: 0 AN: 26966

American (AMR) AF: 0.00 AC: 0 AN: 30436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23616

East Asian (EAS) AF: 0.00 AC: 0 AN: 30264

South Asian (SAS) AF: 0.0000267 AC: 2 AN: 74816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1058952

Other (OTH) AF: 0.00 AC: 0 AN: 55638

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.61
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.096	B
Vest4		0.25
MutPred		0.40		Loss of helix (P = 0.0237)
MVP		0.85
MPC		0.20
ClinPred		0.90	D
GERP RS		3.1
PromoterAI		-0.40	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.21
gMVP		0.62

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: rs973170664; hg19: chr16-89574830;