NM_025137.4:c.6944A>C

Variant names:

• chr15-44565909-T-G
• rs200276333
• NM_025137.4:c.6944A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025137.4(SPG11):​c.6944A>C​(p.Asn2315Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000911 in 1,613,584 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2315K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 4.98
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16873077).

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.6944A>C	p.Asn2315Thr	missense	Exon 38 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6800A>C	p.Asn2267Thr	missense	Exon 38 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.6605A>C	p.Asn2202Thr	missense	Exon 36 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.6944A>C	p.Asn2315Thr	missense	Exon 38 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.6605A>C	p.Asn2202Thr	missense	Exon 36 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6754+1515A>C		intron	N/A	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000136 AC: 34 AN: 249704 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000931 AC: 136 AN: 1461352 Hom.: 0 Cov.: 32 AF XY: 0.0000963 AC XY: 70 AN XY: 726960

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000671 AC: 3 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5706

European-Non Finnish (NFE) AF: 0.0000728 AC: 81 AN: 1111916

Other (OTH) AF: 0.0000663 AC: 4 AN: 60346

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74442

African (AFR) AF: 0.0000241 AC: 1 AN: 41524

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000753 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	1	Hereditary spastic paraplegia 11 (2)
-	1	-	Amyotrophic lateral sclerosis type 5 (1)
-	1	-	Charcot-Marie-Tooth disease axonal type 2X (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.78
MPC		0.23
ClinPred		0.39	T
GERP RS		6.1
Varity_R		0.39
gMVP		0.57
Mutation Taster		=68/32	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: rs200276333; hg19: chr15-44858107;