NM_003119.4:c.18G>C

Variant names:

• chr16-89508435-G-C
• rs748504736
• NM_003119.4:c.18G>C
• SPG7 p.Leu6Leu

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_003119.4(SPG7):​c.18G>C​(p.Leu6Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000467 in 1,498,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: SPG7 NM_003119.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• 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: G2P, Orphanet, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal dominant optic atrophy

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000261118 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP7: Synonymous conserved (PhyloP=2.56 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.18G>C	p.Leu6Leu	synonymous	Exon 1 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.18G>C	p.Leu6Leu	synonymous	Exon 1 of 18	NP_001350779.1	A0A2R8Y3M4
	SPG7	NM_199367.3		c.18G>C	p.Leu6Leu	synonymous	Exon 1 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.18G>C	p.Leu6Leu	synonymous	Exon 1 of 17	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.18G>C	p.Leu6Leu	synonymous	Exon 1 of 17	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000341316.6	TSL:1	c.18G>C	p.Leu6Leu	synonymous	Exon 1 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000207 AC: 2 AN: 96416 AF XY: 0.0000369

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000286

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000446 AC: 6 AN: 1346374 Hom.: 0 Cov.: 31 AF XY: 0.00000602 AC XY: 4 AN XY: 664002

African (AFR) AF: 0.00 AC: 0 AN: 27178

American (AMR) AF: 0.00 AC: 0 AN: 31916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23828

East Asian (EAS) AF: 0.00 AC: 0 AN: 31138

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00000470 AC: 5 AN: 1062970

Other (OTH) AF: 0.00 AC: 0 AN: 56098

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.4
DANN	Benign	0.70
PhyloP100		2.6
PromoterAI		-0.11	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs748504736; hg19: chr16-89574843;