rs912983346

Variant names:

• chr16-89513037-G-A
• rs912983346
• NM_003119.4:c.376G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89513037-G-A
• chr16-89513037-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_003119.4(SPG7):​c.376G>A​(p.Glu126Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,452,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E126Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89513037-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 424654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.376G>A	p.Glu126Lys	missense_variant, splice_region_variant	Exon 3 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.376G>A	p.Glu126Lys	missense_variant, splice_region_variant	Exon 3 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452280 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721946

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.0000232 AC: 1 AN: 43116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 85506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106552

Other (OTH) AF: 0.0000167 AC: 1 AN: 59926

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	.;T;.;.;.;.;.;.;.;.
Eigen	Benign	0.063
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	.;M;.;.;.;.;.;.;.;M
PhyloP100		4.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	.;.;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.079	.;.;.;.;.;.;.;.;T;T
Sift4G	Benign	0.15	.;.;.;.;.;.;.;.;T;T
Polyphen		0.47, 1.0	.;P;.;.;.;.;.;.;.;D
Vest4		0.44, 0.44
MutPred		0.32		.;Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);Gain of methylation at E126 (P = 0.0061);
MVP		0.91
MPC		0.24
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.91
RBP_regulation_power_radar		3.8
Varity_R		0.22
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 23
DS_DL_spliceai		0.40		Position offset: 0

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

Other links and lift over

dbSNP: rs912983346; hg19: chr16-89579445;