16-89541827-A-G

Variant names:

• chr16-89541827-A-G
• rs457372
• NM_003119.4:c.1325-2821A>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.1325-2821A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,024 control chromosomes in the GnomAD database, including 31,337 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 0.64 (31333 hom., cov: 32)
  • Exomes 𝑓: 0.71 (4 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 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.1325-2821A>G		intron	N/A	NP_003110.1
	SPG7	NM_001363850.1		c.1325-2821A>G		intron	N/A	NP_001350779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.1325-2821A>G		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.1304-2821A>G		intron	N/A	ENSP00000268704.3
	SPG7	ENST00000642334.1		n.*816A>G		non_coding_transcript_exon	Exon 10 of 20	ENSP00000496403.1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97329 AN: 151890 Hom.: 31291 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.588

GnomAD4 exome AF: 0.714 AC: 10 AN: 14 Hom.: 4 Cov.: 0 AF XY: 0.750 AC XY: 9 AN XY: 12

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: 0.750 AC: 3 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.700 AC: 7 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.641 AC: 97424 AN: 152010 Hom.: 31333 Cov.: 32 AF XY: 0.642 AC XY: 47716 AN XY: 74316

African (AFR) AF: 0.642 AC: 26608 AN: 41446

American (AMR) AF: 0.613 AC: 9364 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2242 AN: 3472

East Asian (EAS) AF: 0.716 AC: 3697 AN: 5162

South Asian (SAS) AF: 0.713 AC: 3433 AN: 4818

European-Finnish (FIN) AF: 0.642 AC: 6782 AN: 10568

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43322 AN: 67948

Other (OTH) AF: 0.590 AC: 1246 AN: 2112

Alfa AF: 0.630 Hom.: 47955

Bravo AF: 0.639

Asia WGS AF: 0.691 AC: 2400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.8
DANN	Benign	0.61
PhyloP100		0.085
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: rs457372; hg19: chr16-89608235;