15-44584469-A-T

Position:

• chr15-44584469-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025137.4(SPG11):​c.5211T>A​(p.Asn1737Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N1737N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.740

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062570244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.5211T>A	p.Asn1737Lys	missense_variant	30/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.5211T>A	p.Asn1737Lys	missense_variant	30/40	1	NM_025137.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2020

The p.N1737K variant (also known as c.5211T>A), located in coding exon 30 of the SPG11 gene, results from a T to A substitution at nucleotide position 5211. The asparagine at codon 1737 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1737 of the SPG11 protein (p.Asn1737Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 406516). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.041	T;.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M;M;.;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.50	T;T;T;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.17	B;.;B;.
Vest4		0.37
MutPred		0.33		Gain of methylation at N1737 (P = 0.0058);Gain of methylation at N1737 (P = 0.0058);Gain of methylation at N1737 (P = 0.0058);Gain of methylation at N1737 (P = 0.0058);
MVP		0.51
MPC		0.24
ClinPred		0.13	T
GERP RS		4.6
Varity_R		0.18
gMVP		0.23

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: rs1024346199; hg19: chr15-44876667;