rs149003934

chr15-44573595-C-Achr15-44573595-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025137.4(SPG11):c.6157G>T(p.Val2053Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2053M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28594482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.6157G>T	p.Val2053Leu	missense_variant	32/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.6157G>T	p.Val2053Leu	missense_variant	32/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.084	T;T;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.41
MutPred		0.41		Gain of disorder (P = 0.1515);Gain of disorder (P = 0.1515);Gain of disorder (P = 0.1515);
MVP		0.72
MPC		0.19
ClinPred		0.78	D
GERP RS		6.2
Varity_R		0.098
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs149003934; hg19: chr15-44865793;