rs2460456

Variant names:

• chr16-89535485-C-T
• rs2460456
• NM_003119.4:c.1324+2849C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003119.4(SPG7):​c.1324+2849C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 152,100 control chromosomes in the GnomAD database, including 18,007 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (18007 hom., cov: 33)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.900
• Publications: 17 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

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.1324+2849C>T		intron	N/A	NP_003110.1
	SPG7	NM_001363850.1		c.1324+2849C>T		intron	N/A	NP_001350779.1
	SPG7	NM_199367.3		c.1325-1280C>T		intron	N/A	NP_955399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.1324+2849C>T		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.1303+2849C>T		intron	N/A	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.1325-1280C>T		intron	N/A	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72171 AN: 151982 Hom.: 17999 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.441

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.475 AC: 72200 AN: 152100 Hom.: 18007 Cov.: 33 AF XY: 0.475 AC XY: 35294 AN XY: 74352

African (AFR) AF: 0.335 AC: 13876 AN: 41478

American (AMR) AF: 0.438 AC: 6696 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1712 AN: 3468

East Asian (EAS) AF: 0.381 AC: 1965 AN: 5160

South Asian (SAS) AF: 0.460 AC: 2223 AN: 4832

European-Finnish (FIN) AF: 0.571 AC: 6046 AN: 10588

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38136 AN: 67982

Other (OTH) AF: 0.444 AC: 940 AN: 2116

Alfa AF: 0.515 Hom.: 29092

Bravo AF: 0.460

Asia WGS AF: 0.415 AC: 1444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.56
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2460456; hg19: chr16-89601893;