16-89524042-A-T

Variant names:

• chr16-89524042-A-T
• rs377268309
• NM_003119.4:c.413A>T

Variant summary

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

The NM_003119.4(SPG7):​c.413A>T​(p.Tyr138Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,260 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.11

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.413A>T	p.Tyr138Phe	missense_variant	Exon 4 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.413A>T	p.Tyr138Phe	missense_variant	Exon 4 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461260 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726900

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.;.;.;.;.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.84	.;.;.;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.63	.;.;.;.;.;.;.;.;.;T;T
Sift4G	Benign	0.70	.;.;.;.;.;.;.;.;.;T;T
Polyphen		0.79, 0.98	.;.;P;.;.;.;.;.;.;.;D
Vest4		0.49, 0.50
MutPred		0.40		.;.;Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);Loss of phosphorylation at Y138 (P = 0.0392);
MVP		0.65
MPC		0.30
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.27
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: rs377268309; hg19: chr16-89590450;