16-89508426-G-T

Variant names:

• chr16-89508426-G-T
• rs553241838
• NM_003119.4:c.9G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003119.4(SPG7):​c.9G>T​(p.Val3Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,480,564 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V3V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (24 hom.)
• Consequence: SPG7 NM_003119.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.98
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-89508426-G-T is Benign according to our data. Variant chr16-89508426-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1742/152166) while in subpopulation AFR AF = 0.0395 (1642/41528). AF 95% confidence interval is 0.0379. There are 37 homozygotes in GnomAd4. There are 814 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AD,AR gene

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.9G>T	p.Val3Val	synonymous	Exon 1 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.9G>T	p.Val3Val	synonymous	Exon 1 of 18	NP_001350779.1	A0A2R8Y3M4
	SPG7	NM_199367.3		c.9G>T	p.Val3Val	synonymous	Exon 1 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.9G>T	p.Val3Val	synonymous	Exon 1 of 17	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.9G>T	p.Val3Val	synonymous	Exon 1 of 17	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000341316.6	TSL:1	c.9G>T	p.Val3Val	synonymous	Exon 1 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1734 AN: 152058 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00116 AC: 102 AN: 87752 AF XY: 0.000823

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00104 AC: 1383 AN: 1328398 Hom.: 24 Cov.: 31 AF XY: 0.000886 AC XY: 580 AN XY: 654814

African (AFR) AF: 0.0391 AC: 1047 AN: 26754

American (AMR) AF: 0.00290 AC: 85 AN: 29360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23338

East Asian (EAS) AF: 0.00 AC: 0 AN: 29864

South Asian (SAS) AF: 0.0000814 AC: 6 AN: 73722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33210

Middle Eastern (MID) AF: 0.00306 AC: 12 AN: 3926

European-Non Finnish (NFE) AF: 0.0000750 AC: 79 AN: 1053052

Other (OTH) AF: 0.00279 AC: 154 AN: 55172

GnomAD4 genome AF: 0.0114 AC: 1742 AN: 152166 Hom.: 37 Cov.: 33 AF XY: 0.0109 AC XY: 814 AN XY: 74400

African (AFR) AF: 0.0395 AC: 1642 AN: 41528

American (AMR) AF: 0.00432 AC: 66 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67982

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00867 Hom.: 3

Bravo AF: 0.0133

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.20
DANN	Benign	0.55
PhyloP100		-3.0
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs553241838; hg19: chr16-89574834;