rs746053679

Positions:

• chr16-89513038-G-A
• chr16-89513038-G-C
• chr16-89513038-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_003119.4(SPG7):​c.376+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000138 in 1,451,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPG7 NM_003119.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03726968 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.376+1G>A		splice_donor_variant, intron_variant		ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.376+1G>A		splice_donor_variant, intron_variant			NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000873 AC: 2 AN: 229136 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000622

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000465

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: 22
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746053679; hg19: chr16-89579446; COSMIC: COSV99244516; COSMIC: COSV99244516;