rs3803679

Variant names:

• chr16-89524259-T-C
• rs3803679
• NM_003119.4:c.618+12T>C

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.618+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,604,872 control chromosomes in the GnomAD database, including 165,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16468 hom., cov: 30)
  • Exomes 𝑓: 0.45 (149046 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.28
• Publications: 13 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=-0.93).
• BP6: Variant 16-89524259-T-C is Benign according to our data. Variant chr16-89524259-T-C is described in ClinVar as Benign. ClinVar VariationId is 258910.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: 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.618+12T>C		intron	N/A	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.618+12T>C		intron	N/A	NP_001350779.1	A0A2R8Y3M4
	SPG7	NM_199367.3		c.618+12T>C		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.618+12T>C		intron	N/A	ENSP00000495795.2	Q9UQ90-1
	SPG7	ENST00000268704.7	TSL:1	c.618+12T>C		intron	N/A	ENSP00000268704.3	A0A2U3TZH1
	SPG7	ENST00000341316.6	TSL:1	c.618+12T>C		intron	N/A	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70002 AN: 151138 Hom.: 16443 Cov.: 30

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.526

GnomAD2 exomes AF: 0.475 AC: 117836 AN: 247950 AF XY: 0.484

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.677

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.448 AC: 651194 AN: 1453616 Hom.: 149046 Cov.: 47 AF XY: 0.453 AC XY: 327182 AN XY: 722100

African (AFR) AF: 0.432 AC: 14291 AN: 33092

American (AMR) AF: 0.395 AC: 17623 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13163 AN: 25916

East Asian (EAS) AF: 0.689 AC: 27270 AN: 39560

South Asian (SAS) AF: 0.560 AC: 48114 AN: 85938

European-Finnish (FIN) AF: 0.456 AC: 23825 AN: 52304

Middle Eastern (MID) AF: 0.561 AC: 2533 AN: 4512

European-Non Finnish (NFE) AF: 0.429 AC: 475636 AN: 1107728

Other (OTH) AF: 0.479 AC: 28739 AN: 59964

GnomAD4 genome AF: 0.463 AC: 70070 AN: 151256 Hom.: 16468 Cov.: 30 AF XY: 0.468 AC XY: 34558 AN XY: 73900

African (AFR) AF: 0.427 AC: 17499 AN: 40974

American (AMR) AF: 0.487 AC: 7408 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1722 AN: 3464

East Asian (EAS) AF: 0.672 AC: 3447 AN: 5128

South Asian (SAS) AF: 0.566 AC: 2711 AN: 4790

European-Finnish (FIN) AF: 0.456 AC: 4793 AN: 10516

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.454 AC: 30788 AN: 67876

Other (OTH) AF: 0.527 AC: 1107 AN: 2100

Alfa AF: 0.465 Hom.: 3055

Bravo AF: 0.461

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary spastic paraplegia 7 (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.086
DANN	Benign	0.17
PhyloP100		-1.3
PromoterAI		-0.00030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs3803679; hg19: chr16-89590667;