rs535030441

Variant names:

• chr16-89508421-G-A
• rs535030441
• NM_003119.4:c.4G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89508421-G-A
• chr16-89508421-G-C
• chr16-89508421-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001363850.1(SPG7):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,490,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: SPG7 NM_001363850.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 1.39
• Publications: 1 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

ENSG00000261118 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034443736).
• BP6: Variant 16-89508421-G-A is Benign according to our data. Variant chr16-89508421-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215198.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363850.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.4G>A	p.Ala2Thr	missense	Exon 1 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.4G>A	p.Ala2Thr	missense	Exon 1 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.4G>A	p.Ala2Thr	missense	Exon 1 of 10	NP_955399.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.4G>A	p.Ala2Thr	missense	Exon 1 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.4G>A	p.Ala2Thr	missense	Exon 1 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.4G>A	p.Ala2Thr	missense	Exon 1 of 10	ENSP00000341157.2

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000691

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000731 AC: 66 AN: 90242 AF XY: 0.000627

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000584

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.000739 AC: 989 AN: 1338014 Hom.: 0 Cov.: 31 AF XY: 0.000714 AC XY: 471 AN XY: 659790

African (AFR) AF: 0.00315 AC: 85 AN: 26968

American (AMR) AF: 0.00194 AC: 59 AN: 30426

Ashkenazi Jewish (ASJ) AF: 0.0000423 AC: 1 AN: 23616

East Asian (EAS) AF: 0.00 AC: 0 AN: 30264

South Asian (SAS) AF: 0.0000267 AC: 2 AN: 74830

European-Finnish (FIN) AF: 0.000180 AC: 6 AN: 33418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3950

European-Non Finnish (NFE) AF: 0.000740 AC: 784 AN: 1058908

Other (OTH) AF: 0.000935 AC: 52 AN: 55634

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74420

African (AFR) AF: 0.00308 AC: 128 AN: 41556

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 67976

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00157

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000221 AC: 5

Asia WGS AF: 0.000580 AC: 2 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	Hereditary spastic paraplegia 7 (2)
-	-	2	not specified (2)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	0.071
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.89	P
Vest4		0.28
MVP		0.88
MPC		0.20
ClinPred		0.16	T
GERP RS		3.5
PromoterAI		-0.61	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.61
Mutation Taster		=87/13	polymorphism

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: rs535030441; hg19: chr16-89574829;