15-44663584-T-C

Variant names:

• chr15-44663584-T-C
• rs34255962
• NM_025137.4:c.64A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000261866.12(SPG11):​c.64A>G​(p.Met22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000646 in 1,596,660 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. M22T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: SPG11 ENST00000261866.12 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.02
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004727304).
• BP6: Variant 15-44663584-T-C is Benign according to our data. Variant chr15-44663584-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 316118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00331 (505/152344) while in subpopulation AFR AF = 0.0118 (490/41582). AF 95% confidence interval is 0.0109. There are 6 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261866.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	NM_025137.4	MANE Select	c.64A>G	p.Met22Val	missense	Exon 1 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.64A>G	p.Met22Val	missense	Exon 1 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.64A>G	p.Met22Val	missense	Exon 1 of 38	NP_001153699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.64A>G	p.Met22Val	missense	Exon 1 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.64A>G	p.Met22Val	missense	Exon 1 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.64A>G	p.Met22Val	missense	Exon 1 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 500 AN: 152226 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000590 AC: 124 AN: 210126 AF XY: 0.000412

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.000311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000364 AC: 526 AN: 1444316 Hom.: 3 Cov.: 32 AF XY: 0.000313 AC XY: 225 AN XY: 717706

African (AFR) AF: 0.0134 AC: 445 AN: 33300

American (AMR) AF: 0.000486 AC: 21 AN: 43210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39260

South Asian (SAS) AF: 0.0000828 AC: 7 AN: 84550

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46444

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106352

Other (OTH) AF: 0.000719 AC: 43 AN: 59764

GnomAD4 genome AF: 0.00331 AC: 505 AN: 152344 Hom.: 6 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74510

African (AFR) AF: 0.0118 AC: 490 AN: 41582

American (AMR) AF: 0.000784 AC: 12 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000407 Hom.: 1

Bravo AF: 0.00357

ESP6500AA AF: 0.00813 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000722 AC: 86

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	8.8
DANN	Benign	0.61
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.16
Sift	Benign	0.047	D
Sift4G	Uncertain	0.050	T
Polyphen		0.0	B
Vest4		0.23
MVP		0.58
MPC		0.037
ClinPred		0.032	T
GERP RS		4.6
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.48
Mutation Taster		=100/0	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: rs34255962; hg19: chr15-44955782;