chr16-89553778-C-G

Position:

• chr16-89553778-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003119.4(SPG7):​c.1937-16C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,098 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (21 hom.)
• Consequence: SPG7 NM_003119.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0670

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 -16 ACMG points.

• BP6: Variant 16-89553778-C-G is Benign according to our data. Variant chr16-89553778-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 139247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89553778-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0059 (899/152312) while in subpopulation AFR AF= 0.0161 (670/41564). AF 95% confidence interval is 0.0151. There are 3 homozygotes in gnomad4. There are 441 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1937-16C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000645818.2	NP_003110.1
SPG7	NM_001363850.1	c.1937-16C>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001350779.1
SPG7	XM_047434537.1	c.1064-16C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_047290493.1
SPG7	XM_047434540.1	c.623-16C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1937-16C>G		splice_polypyrimidine_tract_variant, intron_variant			NM_003119.4	ENSP00000495795	P2

Frequencies

GnomAD3 genomes AF: 0.00585 AC: 890 AN: 152194 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00328 AC: 819 AN: 249890 Hom.: 5 AF XY: 0.00297 AC XY: 402 AN XY: 135470

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00228 AC: 3331 AN: 1460786 Hom.: 21 Cov.: 32 AF XY: 0.00224 AC XY: 1629 AN XY: 726722

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.000419

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74474

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00213

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00702

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary spastic paraplegia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	11
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -20

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

Publications

LitVar

Other links and lift over

dbSNP: rs74590011; hg19: chr16-89620186; COSMIC: COSV51953139; COSMIC: COSV51953139;