16-89537178-A-G

Variant names:

• chr16-89537178-A-G
• rs382745
• ENST00000341316.6:c.*268A>G

Variant summary

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

The NM_199367.3(SPG7):​c.*268A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 1,445,254 control chromosomes in the GnomAD database, including 148,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17155 hom., cov: 32)
  • Exomes 𝑓: 0.45 (130950 hom.)
• Consequence: SPG7 NM_199367.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0250
• Publications: 47 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=-0.98).
• BP6: Variant 16-89537178-A-G is Benign according to our data. Variant chr16-89537178-A-G is described in ClinVar as Benign. ClinVar VariationId is 684094.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_199367.3. 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.1324+4542A>G		intron	N/A	NP_003110.1
	SPG7	NM_199367.3		c.*268A>G		3_prime_UTR	Exon 10 of 10	NP_955399.1
	SPG7	NM_001363850.1		c.1324+4542A>G		intron	N/A	NP_001350779.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000341316.6	TSL:1	c.*268A>G		3_prime_UTR	Exon 10 of 10	ENSP00000341157.2
	SPG7	ENST00000645818.2	MANE Select	c.1324+4542A>G		intron	N/A	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.1303+4542A>G		intron	N/A	ENSP00000268704.3

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71632 AN: 151892 Hom.: 17138 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.532

GnomAD4 exome AF: 0.446 AC: 576290 AN: 1293244 Hom.: 130950 Cov.: 38 AF XY: 0.450 AC XY: 282655 AN XY: 628626

African (AFR) AF: 0.465 AC: 13272 AN: 28536

American (AMR) AF: 0.444 AC: 9662 AN: 21770

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 9747 AN: 19304

East Asian (EAS) AF: 0.693 AC: 24317 AN: 35074

South Asian (SAS) AF: 0.562 AC: 35433 AN: 63046

European-Finnish (FIN) AF: 0.454 AC: 13616 AN: 30008

Middle Eastern (MID) AF: 0.555 AC: 2009 AN: 3622

European-Non Finnish (NFE) AF: 0.426 AC: 442496 AN: 1038070

Other (OTH) AF: 0.478 AC: 25738 AN: 53814

GnomAD4 genome AF: 0.472 AC: 71685 AN: 152010 Hom.: 17155 Cov.: 32 AF XY: 0.476 AC XY: 35366 AN XY: 74292

African (AFR) AF: 0.461 AC: 19134 AN: 41488

American (AMR) AF: 0.490 AC: 7482 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1720 AN: 3470

East Asian (EAS) AF: 0.672 AC: 3458 AN: 5148

South Asian (SAS) AF: 0.566 AC: 2722 AN: 4808

European-Finnish (FIN) AF: 0.448 AC: 4733 AN: 10568

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30720 AN: 67948

Other (OTH) AF: 0.533 AC: 1122 AN: 2106

Alfa AF: 0.466 Hom.: 32545

Bravo AF: 0.472

Asia WGS AF: 0.613 AC: 2130 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	-0.98
CADD	Benign	2.0
DANN	Benign	0.48
PhyloP100		0.025
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: rs382745; hg19: chr16-89603586;