chr16-89510638-C-T

Variant names:

• chr16-89510638-C-T
• rs3922633
• NM_003119.4:c.286+46C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003119.4(SPG7):​c.286+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,157,968 control chromosomes in the GnomAD database, including 123,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15585 hom., cov: 32)
  • Exomes 𝑓: 0.46 (108335 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.03
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 16-89510638-C-T is Benign according to our data. Variant chr16-89510638-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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: 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.286+46C>T		intron	N/A	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.286+46C>T		intron	N/A	NP_001350779.1	A0A2R8Y3M4
	SPG7	NM_199367.3		c.286+46C>T		intron	N/A	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.286+46C>T		intron	N/A	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.286+46C>T		intron	N/A	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000341316.6	TSL:1	c.286+46C>T		intron	N/A	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67987 AN: 151820 Hom.: 15570 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.472 AC: 114775 AN: 243216 AF XY: 0.481

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.674

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.459 AC: 461299 AN: 1006030 Hom.: 108335 Cov.: 14 AF XY: 0.465 AC XY: 241691 AN XY: 520054

African (AFR) AF: 0.385 AC: 9523 AN: 24728

American (AMR) AF: 0.395 AC: 17256 AN: 43686

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 11787 AN: 23176

East Asian (EAS) AF: 0.692 AC: 26042 AN: 37650

South Asian (SAS) AF: 0.559 AC: 43083 AN: 77036

European-Finnish (FIN) AF: 0.448 AC: 23257 AN: 51952

Middle Eastern (MID) AF: 0.579 AC: 2842 AN: 4910

European-Non Finnish (NFE) AF: 0.438 AC: 305509 AN: 697292

Other (OTH) AF: 0.482 AC: 22000 AN: 45600

GnomAD4 genome AF: 0.448 AC: 68037 AN: 151938 Hom.: 15585 Cov.: 32 AF XY: 0.453 AC XY: 33620 AN XY: 74224

African (AFR) AF: 0.378 AC: 15670 AN: 41428

American (AMR) AF: 0.484 AC: 7373 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1726 AN: 3472

East Asian (EAS) AF: 0.670 AC: 3456 AN: 5158

South Asian (SAS) AF: 0.564 AC: 2717 AN: 4816

European-Finnish (FIN) AF: 0.446 AC: 4701 AN: 10552

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30694 AN: 67948

Other (OTH) AF: 0.520 AC: 1101 AN: 2116

Alfa AF: 0.458 Hom.: 20228

Bravo AF: 0.446

Asia WGS AF: 0.610 AC: 2119 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.21
PhyloP100		-1.0
PromoterAI		0.046	Neutral
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: rs3922633; hg19: chr16-89577046; COSMIC: COSV51948740; COSMIC: COSV51948740;