NM_003119.4:c.185G>T

Variant names:

• chr16-89510491-G-T
• rs143294686
• NM_003119.4:c.185G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003119.4(SPG7):​c.185G>T​(p.Ser62Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on 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. S62N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000061 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPG7 NM_003119.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003480
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24256301).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.185G>T	p.Ser62Ile	missense splice_region	Exon 2 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.185G>T	p.Ser62Ile	missense splice_region	Exon 2 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.185G>T	p.Ser62Ile	missense splice_region	Exon 2 of 10	NP_955399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.185G>T	p.Ser62Ile	missense splice_region	Exon 2 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.185G>T	p.Ser62Ile	missense splice_region	Exon 2 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.185G>T	p.Ser62Ile	missense splice_region	Exon 2 of 10	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000426 AC: 1 AN: 234826 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000927

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000613 AC: 8 AN: 1305356 Hom.: 0 Cov.: 27 AF XY: 0.00000153 AC XY: 1 AN XY: 655112

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29584

American (AMR) AF: 0.00 AC: 0 AN: 40836

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24720

East Asian (EAS) AF: 0.00 AC: 0 AN: 38728

South Asian (SAS) AF: 0.00 AC: 0 AN: 80628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5340

European-Non Finnish (NFE) AF: 0.00000714 AC: 7 AN: 980962

Other (OTH) AF: 0.00 AC: 0 AN: 54922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 146044 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70696

African (AFR) AF: 0.00 AC: 0 AN: 39478

American (AMR) AF: 0.00 AC: 0 AN: 14696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.00 AC: 0 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66844

Other (OTH) AF: 0.00 AC: 0 AN: 1990

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.24	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.13
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.19	T
Polyphen		0.64	P
Vest4		0.39
MutPred		0.33		Gain of stability (P = 0.0068)
MVP		0.90
MPC		0.32
ClinPred		0.94	D
GERP RS		3.3
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.0
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: rs143294686; hg19: chr16-89576899;