16-89508422-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003119.4(SPG7):​c.5C>A​(p.Ala2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,338,066 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.607

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.5C>A	p.Ala2Asp	missense_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.5C>A	p.Ala2Asp	missense_variant	Exon 1 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000221 AC: 2 AN: 90296 Hom.: 0 AF XY: 0.0000196 AC XY: 1 AN XY: 51052

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: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1338066 Hom.: 0 Cov.: 31 AF XY: 0.00000455 AC XY: 3 AN XY: 659848

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: 0.0000535

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.069	T;.;.;.;.;.;.;.;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.41	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;.;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.0	.;.;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D
Polyphen		0.99	D;.;.;.;.;.;.;.;.;D
Vest4		0.57, 0.58
MutPred		0.33		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.93
MPC		0.31
ClinPred		0.67	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.81

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: rs973170664; hg19: chr16-89574830;