16-89529698-C-T

Variant names:

• chr16-89529698-C-T
• rs3803676
• NM_003119.4:c.861+119C>T

Variant summary

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

The ENST00000645818.2(SPG7):​c.861+119C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 774,036 control chromosomes in the GnomAD database, including 85,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14623 hom., cov: 33)
  • Exomes 𝑓: 0.47 (70769 hom.)
• Consequence: SPG7 ENST00000645818.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.474
• Publications: 25 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=-0.88).
• BP6: Variant 16-89529698-C-T is Benign according to our data. Variant chr16-89529698-C-T is described in ClinVar as Benign. ClinVar VariationId is 1230890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000645818.2. 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.861+119C>T		intron	N/A	NP_003110.1
	SPG7	NM_001363850.1		c.861+119C>T		intron	N/A	NP_001350779.1
	SPG7	NM_199367.3		c.861+119C>T		intron	N/A	NP_955399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.861+119C>T		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.861+119C>T		intron	N/A	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.861+119C>T		intron	N/A	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65304 AN: 151968 Hom.: 14614 Cov.: 33

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.506

GnomAD4 exome AF: 0.469 AC: 291658 AN: 621950 Hom.: 70769 Cov.: 7 AF XY: 0.476 AC XY: 157928 AN XY: 331888

African (AFR) AF: 0.322 AC: 5408 AN: 16776

American (AMR) AF: 0.400 AC: 13870 AN: 34662

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 10346 AN: 20364

East Asian (EAS) AF: 0.693 AC: 22327 AN: 32222

South Asian (SAS) AF: 0.556 AC: 35205 AN: 63292

European-Finnish (FIN) AF: 0.448 AC: 19293 AN: 43110

Middle Eastern (MID) AF: 0.573 AC: 1983 AN: 3462

European-Non Finnish (NFE) AF: 0.446 AC: 167596 AN: 375562

Other (OTH) AF: 0.481 AC: 15630 AN: 32500

GnomAD4 genome AF: 0.430 AC: 65335 AN: 152086 Hom.: 14623 Cov.: 33 AF XY: 0.435 AC XY: 32350 AN XY: 74316

African (AFR) AF: 0.317 AC: 13146 AN: 41480

American (AMR) AF: 0.474 AC: 7243 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1725 AN: 3472

East Asian (EAS) AF: 0.671 AC: 3471 AN: 5170

South Asian (SAS) AF: 0.563 AC: 2717 AN: 4824

European-Finnish (FIN) AF: 0.445 AC: 4700 AN: 10554

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30665 AN: 67982

Other (OTH) AF: 0.507 AC: 1070 AN: 2112

Alfa AF: 0.451 Hom.: 20228

Bravo AF: 0.425

Asia WGS AF: 0.601 AC: 2089 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.79
DANN	Benign	0.50
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs3803676; hg19: chr16-89596106; COSMIC: COSV51956117; COSMIC: COSV51956117;