15-44585807-C-G

Variant names:

• chr15-44585807-C-G
• NM_025137.4:c.4950G>C
• SPG11 p.Lys1650Asn

Variant summary

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

The NM_025137.4(SPG11):​c.4950G>C​(p.Lys1650Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. K1650K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• 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: G2P, ClinGen, Illumina, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4950G>C	p.Lys1650Asn	missense	Exon 29 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.4950G>C	p.Lys1650Asn	missense	Exon 29 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.4950G>C	p.Lys1650Asn	missense	Exon 29 of 38	NP_001153699.1	Q96JI7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.4950G>C	p.Lys1650Asn	missense	Exon 29 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.4950G>C	p.Lys1650Asn	missense	Exon 29 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.4950G>C	p.Lys1650Asn	missense	Exon 29 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.11	T
Sift4G	Benign	0.084	T
Varity_R		0.12
gMVP		0.29
Mutation Taster		=73/27	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-44878005;