15-44657131-T-C

Variant names:

• chr15-44657131-T-C
• rs75309308
• NM_025137.4:c.833A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025137.4(SPG11):​c.833A>G​(p.Asn278Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,614,044 control chromosomes in the GnomAD database, including 209 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N278I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (183 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 0.00700
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014099479).
• BP6: Variant 15-44657131-T-C is Benign according to our data. Variant chr15-44657131-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 316111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0826 is higher than 0.05.

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.833A>G	p.Asn278Ser	missense	Exon 4 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.833A>G	p.Asn278Ser	missense	Exon 4 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.833A>G	p.Asn278Ser	missense	Exon 4 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.833A>G	p.Asn278Ser	missense	Exon 4 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.833A>G	p.Asn278Ser	missense	Exon 4 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.833A>G	p.Asn278Ser	missense	Exon 4 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 576 AN: 152064 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0896

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00842 AC: 2116 AN: 251388 AF XY: 0.00787

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00276 AC: 4035 AN: 1461864 Hom.: 183 Cov.: 31 AF XY: 0.00273 AC XY: 1985 AN XY: 727230

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0781 AC: 3101 AN: 39696

South Asian (SAS) AF: 0.00438 AC: 378 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1112000

Other (OTH) AF: 0.00811 AC: 490 AN: 60392

GnomAD4 genome AF: 0.00377 AC: 573 AN: 152180 Hom.: 26 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74404

African (AFR) AF: 0.000795 AC: 33 AN: 41522

American (AMR) AF: 0.00111 AC: 17 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0893 AC: 463 AN: 5186

South Asian (SAS) AF: 0.00789 AC: 38 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.000394 Hom.: 3

Bravo AF: 0.00424

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00776 AC: 942

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Hereditary spastic paraplegia 11 (4)
-	-	2	not specified (2)
-	-	1	Amyotrophic lateral sclerosis type 5 (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2X (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.6
DANN	Benign	0.40
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.0070
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.013
Sift	Benign	0.49	T
Sift4G	Benign	0.91	T
Polyphen		0.012	B
Vest4		0.30
MVP		0.13
MPC		0.032
ClinPred		0.0015	T
GERP RS		-0.41
Varity_R		0.029
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75309308; hg19: chr15-44949329; COSMIC: COSV56001672;