rs771130240

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K113K) has been classified as Likely benign.

• 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
• 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: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 VariationId is 573952.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.338A>G	p.Lys113Arg	missense	Exon 3 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.338A>G	p.Lys113Arg	missense	Exon 3 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.338A>G	p.Lys113Arg	missense	Exon 3 of 10	NP_955399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.338A>G	p.Lys113Arg	missense	Exon 3 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.338A>G	p.Lys113Arg	missense	Exon 3 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.338A>G	p.Lys113Arg	missense	Exon 3 of 10	ENSP00000341157.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 248138 AF XY: 0.0000967

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.000515 AC: 23 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111248

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000782 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.23
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.076
Sift	Benign	0.21	T
Sift4G	Benign	0.22	T
Polyphen		0.094	B
Vest4		0.13
MutPred		0.27		Loss of methylation at K113 (P = 0.0051)
MVP		0.64
MPC		0.17
ClinPred		0.029	T
GERP RS		-2.1
PromoterAI		-0.030	Neutral
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

Other links and lift over

dbSNP: rs771130240; hg19: chr16-89579407;