rs80324518

Variant names:

• chr16-89548126-C-T
• rs80324518
• NM_003119.4:c.1663+13C>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.1663+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 1,579,268 control chromosomes in the GnomAD database, including 5,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (292 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5291 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.733
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-89548126-C-T is Benign according to our data. Variant chr16-89548126-C-T is described in ClinVar as Benign. ClinVar VariationId is 139242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0859 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.1663+13C>T		intron	N/A	NP_003110.1
	SPG7	NM_001363850.1		c.1663+13C>T		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.1663+13C>T		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.1642+13C>T		intron	N/A	ENSP00000268704.3
	SPG7	ENST00000563218.6	TSL:5	n.735C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8196 AN: 152212 Hom.: 292 Cov.: 33

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.0464

GnomAD2 exomes AF: 0.0537 AC: 12881 AN: 239650 AF XY: 0.0541

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0605

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0892

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0796 AC: 113564 AN: 1426938 Hom.: 5291 Cov.: 26 AF XY: 0.0776 AC XY: 55231 AN XY: 711702

African (AFR) AF: 0.0121 AC: 400 AN: 32958

American (AMR) AF: 0.0195 AC: 870 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 1488 AN: 25982

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39574

South Asian (SAS) AF: 0.00885 AC: 760 AN: 85864

European-Finnish (FIN) AF: 0.0696 AC: 2914 AN: 41868

Middle Eastern (MID) AF: 0.0275 AC: 157 AN: 5718

European-Non Finnish (NFE) AF: 0.0946 AC: 103150 AN: 1090756

Other (OTH) AF: 0.0642 AC: 3822 AN: 59526

GnomAD4 genome AF: 0.0538 AC: 8196 AN: 152330 Hom.: 292 Cov.: 33 AF XY: 0.0508 AC XY: 3784 AN XY: 74500

African (AFR) AF: 0.0160 AC: 665 AN: 41584

American (AMR) AF: 0.0266 AC: 407 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4832

European-Finnish (FIN) AF: 0.0645 AC: 684 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0878 AC: 5972 AN: 68026

Other (OTH) AF: 0.0459 AC: 97 AN: 2114

Alfa AF: 0.0712 Hom.: 83

Bravo AF: 0.0494

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hereditary spastic paraplegia 7 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.27
DANN	Benign	0.60
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs80324518; hg19: chr16-89614534;