16-89522080-A-G

Variant names:

• chr16-89522080-A-G
• rs11862081
• NM_003119.4:c.377-1926A>G

Variant summary

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

The NM_003119.4(SPG7):​c.377-1926A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 152,138 control chromosomes in the GnomAD database, including 14,779 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 0.43 (14779 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 16 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.655 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.377-1926A>G		intron	N/A	NP_003110.1
	SPG7	NM_001363850.1		c.377-1926A>G		intron	N/A	NP_001350779.1
	SPG7	NM_199367.3		c.377-1926A>G		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.377-1926A>G		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.377-1926A>G		intron	N/A	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.377-1926A>G		intron	N/A	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65623 AN: 152018 Hom.: 14772 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.507

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.432 AC: 65650 AN: 152136 Hom.: 14779 Cov.: 33 AF XY: 0.438 AC XY: 32542 AN XY: 74364

African (AFR) AF: 0.318 AC: 13194 AN: 41506

American (AMR) AF: 0.476 AC: 7280 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1722 AN: 3468

East Asian (EAS) AF: 0.674 AC: 3488 AN: 5174

South Asian (SAS) AF: 0.564 AC: 2722 AN: 4824

European-Finnish (FIN) AF: 0.454 AC: 4801 AN: 10580

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30773 AN: 67976

Other (OTH) AF: 0.508 AC: 1072 AN: 2112

Alfa AF: 0.440 Hom.: 23193

Bravo AF: 0.426

Asia WGS AF: 0.601 AC: 2089 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.2
DANN	Benign	0.68
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs11862081; hg19: chr16-89588488;