15-44567546-C-T

Variant names:

• chr15-44567546-C-T
• rs144165094
• NM_025137.4:c.6632G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_025137.4(SPG11):​c.6632G>A​(p.Arg2211His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R2211C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.02
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007485807).
• BP6: Variant 15-44567546-C-T is Benign according to our data. Variant chr15-44567546-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241598.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000934 (1365/1461860) while in subpopulation MID AF = 0.00104 (6/5768). AF 95% confidence interval is 0.000873. There are 0 homozygotes in GnomAdExome4. There are 666 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

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.6632G>A	p.Arg2211His	missense	Exon 36 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6488G>A	p.Arg2163His	missense	Exon 36 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.6293G>A	p.Arg2098His	missense	Exon 34 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.6632G>A	p.Arg2211His	missense	Exon 36 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.6293G>A	p.Arg2098His	missense	Exon 34 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6632G>A	p.Arg2211His	missense	Exon 36 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.000836 AC: 127 AN: 151942 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000815 AC: 205 AN: 251438 AF XY: 0.000883

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00774

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000934 AC: 1365 AN: 1461860 Hom.: 0 Cov.: 34 AF XY: 0.000916 AC XY: 666 AN XY: 727238

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00681 AC: 178 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000920 AC: 1023 AN: 1111984

Other (OTH) AF: 0.00149 AC: 90 AN: 60394

GnomAD4 genome AF: 0.000835 AC: 127 AN: 152060 Hom.: 0 Cov.: 31 AF XY: 0.000807 AC XY: 60 AN XY: 74344

African (AFR) AF: 0.000410 AC: 17 AN: 41462

American (AMR) AF: 0.000524 AC: 8 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000918

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000815 AC: 99

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spastic paraplegia 11 (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.14	B
Vest4		0.38
MVP		0.52
MPC		0.042
ClinPred		0.017	T
GERP RS		3.1
Varity_R		0.042
gMVP		0.32
Mutation Taster		=84/16	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: rs144165094; hg19: chr15-44859744;