ENST00000646303.1:c.51+428G>A

Variant names:

• chr16-89508168-G-A
• rs4785684
• ENST00000646303.1:c.51+428G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000646303.1(SPG7):​c.51+428G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 365,506 control chromosomes in the GnomAD database, including 39,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (14556 hom., cov: 33)
  • Exomes 𝑓: 0.47 (24847 hom.)
• Consequence: SPG7 ENST00000646303.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.217
• Publications: 18 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-89508168-G-A is Benign according to our data. Variant chr16-89508168-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261810.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000646303.1. 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
	LOC101927863	NR_188547.1		n.84+69C>T		intron	N/A
	SPG7	NM_003119.4	MANE Select	c.-250G>A		upstream_gene	N/A	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.-250G>A		upstream_gene	N/A	NP_001350779.1	A0A2R8Y3M4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000646303.1		c.51+428G>A		intron	N/A	ENSP00000494160.1	A0A2R8Y4Y7
	SPG7	ENST00000647079.1		c.-225-2322G>A		intron	N/A	ENSP00000495967.1	A0A2R8Y726
	ENSG00000261118	ENST00000726307.1		n.88+69C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65105 AN: 151772 Hom.: 14551 Cov.: 33

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.504

GnomAD4 exome AF: 0.472 AC: 100770 AN: 213628 Hom.: 24847 Cov.: 2 AF XY: 0.474 AC XY: 51479 AN XY: 108622

African (AFR) AF: 0.306 AC: 1745 AN: 5710

American (AMR) AF: 0.437 AC: 2530 AN: 5794

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 3737 AN: 7458

East Asian (EAS) AF: 0.698 AC: 12519 AN: 17946

South Asian (SAS) AF: 0.537 AC: 2528 AN: 4704

European-Finnish (FIN) AF: 0.443 AC: 8262 AN: 18630

Middle Eastern (MID) AF: 0.533 AC: 593 AN: 1112

European-Non Finnish (NFE) AF: 0.450 AC: 62326 AN: 138422

Other (OTH) AF: 0.471 AC: 6530 AN: 13852

GnomAD4 genome AF: 0.429 AC: 65126 AN: 151878 Hom.: 14556 Cov.: 33 AF XY: 0.434 AC XY: 32241 AN XY: 74218

African (AFR) AF: 0.314 AC: 13010 AN: 41410

American (AMR) AF: 0.476 AC: 7282 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1725 AN: 3470

East Asian (EAS) AF: 0.670 AC: 3432 AN: 5122

South Asian (SAS) AF: 0.564 AC: 2722 AN: 4828

European-Finnish (FIN) AF: 0.445 AC: 4690 AN: 10546

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.451 AC: 30602 AN: 67908

Other (OTH) AF: 0.505 AC: 1064 AN: 2108

Alfa AF: 0.455 Hom.: 16571

Bravo AF: 0.424

Asia WGS AF: 0.598 AC: 2069 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.7
DANN	Benign	0.92
PhyloP100		-0.22
PromoterAI		-0.0071	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4785684; hg19: chr16-89574576;