rs8044175

Variant names:

• chr16-89553289-G-T
• rs8044175
• NM_003119.4:c.1936+154G>T

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.1936+154G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 859,084 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (281 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (153 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.409
• Publications: 4 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=-0.99).
• BP6: Variant 16-89553289-G-T is Benign according to our data. Variant chr16-89553289-G-T is described in ClinVar as Benign. ClinVar VariationId is 677643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1936+154G>T		intron_variant	Intron 14 of 16	ENST00000645818.2	NP_003110.1
SPG7	NM_001363850.1	c.1936+154G>T		intron_variant	Intron 14 of 17		NP_001350779.1
SPG7	XM_047434537.1	c.1063+154G>T		intron_variant	Intron 9 of 12		XP_047290493.1
SPG7	XM_047434540.1	c.622+154G>T		intron_variant	Intron 6 of 8		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1936+154G>T		intron_variant	Intron 14 of 16		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 5366 AN: 152182 Hom.: 272 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.00590 AC: 4168 AN: 706784 Hom.: 153 Cov.: 9 AF XY: 0.00516 AC XY: 1894 AN XY: 366982

African (AFR) AF: 0.118 AC: 2145 AN: 18112

American (AMR) AF: 0.00968 AC: 320 AN: 33066

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 29 AN: 20260

East Asian (EAS) AF: 0.00 AC: 0 AN: 32342

South Asian (SAS) AF: 0.00206 AC: 131 AN: 63476

European-Finnish (FIN) AF: 0.000509 AC: 17 AN: 33388

Middle Eastern (MID) AF: 0.0346 AC: 150 AN: 4338

European-Non Finnish (NFE) AF: 0.00204 AC: 952 AN: 466570

Other (OTH) AF: 0.0120 AC: 424 AN: 35232

GnomAD4 genome AF: 0.0355 AC: 5404 AN: 152300 Hom.: 281 Cov.: 33 AF XY: 0.0345 AC XY: 2569 AN XY: 74484

African (AFR) AF: 0.120 AC: 4974 AN: 41542

American (AMR) AF: 0.0128 AC: 196 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 68036

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0162 Hom.: 129

Bravo AF: 0.0411

Asia WGS AF: 0.0150 AC: 51 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 14, 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	-0.99
CADD	Benign	1.0
DANN	Benign	0.47
PhyloP100		-0.41
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: rs8044175; hg19: chr16-89619697;