16-89517401-C-T

Variant names:

• chr16-89517401-C-T
• rs8052076
• NM_003119.4:c.376+4364C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3 BP6_Moderate BA1

The NM_003119.4(SPG7):​c.376+4364C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 141,026 control chromosomes in the GnomAD database, including 14,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (14138 hom., cov: 30)
  • Exomes 𝑓: 0.49 (13 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.969
• Publications: 14 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 -9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-89517401-C-T is Benign according to our data. Variant chr16-89517401-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169989.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.376+4364C>T		intron_variant	Intron 3 of 16	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.376+4364C>T		intron_variant	Intron 3 of 16		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.423 AC: 59586 AN: 140830 Hom.: 14132 Cov.: 30

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.612

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.497

GnomAD4 exome AF: 0.489 AC: 45 AN: 92 Hom.: 13 Cov.: 0 AF XY: 0.488 AC XY: 40 AN XY: 82

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.571 AC: 8 AN: 14

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.456 AC: 31 AN: 68

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.423 AC: 59606 AN: 140934 Hom.: 14138 Cov.: 30 AF XY: 0.428 AC XY: 29423 AN XY: 68710

African (AFR) AF: 0.310 AC: 11986 AN: 38686

American (AMR) AF: 0.470 AC: 6723 AN: 14304

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1591 AN: 3232

East Asian (EAS) AF: 0.675 AC: 3233 AN: 4790

South Asian (SAS) AF: 0.557 AC: 2438 AN: 4376

European-Finnish (FIN) AF: 0.445 AC: 4328 AN: 9720

Middle Eastern (MID) AF: 0.613 AC: 173 AN: 282

European-Non Finnish (NFE) AF: 0.443 AC: 27811 AN: 62808

Other (OTH) AF: 0.497 AC: 945 AN: 1900

Alfa AF: 0.444 Hom.: 20635

Bravo AF: 0.428

Asia WGS AF: 0.555 AC: 1770 AN: 3196

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 7 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	22
DANN	Benign	0.48
PhyloP100		-0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: -2

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

Other links and lift over

dbSNP: rs8052076; hg19: chr16-89583809;