rs771130240

Variant names:

• chr16-89512999-A-G
• rs771130240
• NM_003119.4:c.338A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_003119.4(SPG7):​c.338A>G​(p.Lys113Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.231

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027846336).
• BP6: Variant 16-89512999-A-G is Benign according to our data. Variant chr16-89512999-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.338A>G	p.Lys113Arg	missense_variant	Exon 3 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.338A>G	p.Lys113Arg	missense_variant	Exon 3 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000101 AC: 25 AN: 248138 Hom.: 0 AF XY: 0.0000967 AC XY: 13 AN XY: 134482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000724

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: 0.0000157 AC: 23 AN: 1460886 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000515

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

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338A>G (p.K113R) alteration is located in exon 3 (coding exon 3) of the SPG7 gene. This alteration results from a A to G substitution at nucleotide position 338, causing the lysine (K) at amino acid position 113 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 7 Benign:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.5
DANN	Benign	0.97
DEOGEN2	Benign	0.053	.;T;.;.;.;.;.;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.028	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.34	.;N;.;.;.;.;.;.;.;.;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.44	.;.;.;.;.;.;.;.;.;N;N
REVEL	Benign	0.076
Sift	Benign	0.21	.;.;.;.;.;.;.;.;.;T;T
Sift4G	Benign	0.22	.;.;.;.;.;.;.;.;.;T;T
Polyphen		0.094, 0.43	.;B;.;.;.;.;.;.;.;.;B
Vest4		0.13, 0.13
MutPred		0.27		.;Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);
MVP		0.64
MPC		0.17
ClinPred		0.029	T
GERP RS		-2.1
Varity_R		0.023
gMVP		0.22

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: rs771130240; hg19: chr16-89579407;