rs372658867

Variant names:

• chr15-44663620-C-A
• rs372658867
• NM_025137.4:c.28G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-44663620-C-A
• chr15-44663620-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025137.4(SPG11):​c.28G>T​(p.Ala10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A10T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.555
• Publications: 0 publications found

Genes affected

SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

SPG11 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• amyotrophic lateral sclerosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2X

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15276873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.28G>T	p.Ala10Ser	missense_variant	Exon 1 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.28G>T	p.Ala10Ser	missense_variant	Exon 1 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1443560 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 717734

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 43588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 84816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108044

Other (OTH) AF: 0.0000167 AC: 1 AN: 59922

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.0064	T;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.53	T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.34	N;N;.;N;.
PhyloP100		0.56
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.14	N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.80	P;.;P;.;.
Vest4		0.28
MutPred		0.28		Gain of glycosylation at A10 (P = 0.0031);Gain of glycosylation at A10 (P = 0.0031);Gain of glycosylation at A10 (P = 0.0031);Gain of glycosylation at A10 (P = 0.0031);Gain of glycosylation at A10 (P = 0.0031);
MVP		0.57
MPC		0.035
ClinPred		0.52	D
GERP RS		4.5
PromoterAI		-0.057	Neutral
Varity_R		0.080
gMVP		0.26
Mutation Taster		=94/6	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: rs372658867; hg19: chr15-44955818;