chr15-44584469-A-T

Variant names:

• chr15-44584469-A-T
• rs1024346199
• NM_025137.4:c.5211T>A

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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. N1737H) has been classified as Uncertain significance.

• 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:3
• Conservation: PhyloP100: 0.740
• 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: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025137.4. 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
	SPG11	NM_025137.4	MANE Select	c.5211T>A	p.Asn1737Lys	missense	Exon 30 of 40	NP_079413.3
	SPG11	NM_001160227.2		c.5211T>A	p.Asn1737Lys	missense	Exon 30 of 38	NP_001153699.1
	SPG11	NM_001411132.1		c.5122-55T>A		intron	N/A	NP_001398061.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.5211T>A	p.Asn1737Lys	missense	Exon 30 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.5211T>A	p.Asn1737Lys	missense	Exon 30 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.5211T>A	p.Asn1737Lys	missense	Exon 30 of 37	ENSP00000396110.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 11 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.74
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.50	T
Sift4G	Benign	0.93	T
Polyphen		0.17	B
Vest4		0.37
MutPred		0.33		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
Mutation Taster		=99/1	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: rs1024346199; hg19: chr15-44876667;