16-89523835-G-A

Variant names:

• chr16-89523835-G-A
• rs3803680
• NM_003119.4:c.377-171G>A

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.377-171G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 875,658 control chromosomes in the GnomAD database, including 95,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14799 hom., cov: 32)
  • Exomes 𝑓: 0.47 (81112 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.122
• Publications: 22 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 16-89523835-G-A is Benign according to our data. Variant chr16-89523835-G-A is described in ClinVar as Benign. ClinVar VariationId is 670124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.377-171G>A		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.377-171G>A		intron_variant	Intron 3 of 16		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65673 AN: 151928 Hom.: 14791 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.477 AC: 67696 AN: 141940 AF XY: 0.486

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.681

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.466 AC: 337504 AN: 723610 Hom.: 81112 Cov.: 10 AF XY: 0.473 AC XY: 180231 AN XY: 380724

African (AFR) AF: 0.327 AC: 6170 AN: 18856

American (AMR) AF: 0.402 AC: 14026 AN: 34872

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 10722 AN: 21064

East Asian (EAS) AF: 0.695 AC: 22716 AN: 32706

South Asian (SAS) AF: 0.558 AC: 36517 AN: 65416

European-Finnish (FIN) AF: 0.459 AC: 15654 AN: 34116

Middle Eastern (MID) AF: 0.577 AC: 2550 AN: 4416

European-Non Finnish (NFE) AF: 0.445 AC: 211683 AN: 475976

Other (OTH) AF: 0.483 AC: 17466 AN: 36188

GnomAD4 genome AF: 0.432 AC: 65700 AN: 152048 Hom.: 14799 Cov.: 32 AF XY: 0.438 AC XY: 32559 AN XY: 74308

African (AFR) AF: 0.320 AC: 13283 AN: 41484

American (AMR) AF: 0.476 AC: 7266 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1723 AN: 3468

East Asian (EAS) AF: 0.673 AC: 3471 AN: 5160

South Asian (SAS) AF: 0.564 AC: 2723 AN: 4824

European-Finnish (FIN) AF: 0.455 AC: 4802 AN: 10560

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

European-Non Finnish (NFE) AF: 0.453 AC: 30766 AN: 67966

Other (OTH) AF: 0.508 AC: 1070 AN: 2108

Alfa AF: 0.446 Hom.: 47031

Bravo AF: 0.427

Asia WGS AF: 0.602 AC: 2091 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.55
DANN	Benign	0.62
PhyloP100		-0.12
PromoterAI		-0.032	Neutral
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: rs3803680; hg19: chr16-89590243;