rs1555611542

chr16-89524249-TGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_003119.4(SPG7):c.618+11_618+68del variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,608,672 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: SPG7 NM_003119.4 splice_donor_5th_base, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.46

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 16-89524249-TGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA-T is Benign according to our data. Variant chr16-89524249-TGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 215504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0021 (319/151870) while in subpopulation AFR AF= 0.00746 (309/41402). AF 95% confidence interval is 0.00678. There are 4 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.618+11_618+68del		splice_donor_5th_base_variant, intron_variant		ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.618+11_618+68del		splice_donor_5th_base_variant, intron_variant			NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 151752 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.00749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000582 AC: 145 AN: 249300 Hom.: 2 AF XY: 0.000378 AC XY: 51 AN XY: 134946

Gnomad AFR exome AF: 0.00871

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000235 AC: 342 AN: 1456802 Hom.: 1 AF XY: 0.000207 AC XY: 150 AN XY: 724144

Gnomad4 AFR exome AF: 0.00854

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000682

GnomAD4 genome AF: 0.00210 AC: 319 AN: 151870 Hom.: 4 Cov.: 30 AF XY: 0.00202 AC XY: 150 AN XY: 74244

Gnomad4 AFR AF: 0.00746

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000843 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SPG7: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2020	This variant is associated with the following publications: (PMID: 22964162) -

Hereditary spastic paraplegia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555611542; hg19: chr16-89590657;