chr15-44572802-T-C

Variant names:

• chr15-44572802-T-C
• rs140824939
• NM_025137.4:c.6224A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025137.4(SPG11):​c.6224A>G​(p.Asn2075Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,613,944 control chromosomes in the GnomAD database, including 15 homozygotes. 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. N2075T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: -0.626
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044772923).
• BP6: Variant 15-44572802-T-C is Benign according to our data. Variant chr15-44572802-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188231.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00264 (401/152130) while in subpopulation AMR AF = 0.00413 (63/15264). AF 95% confidence interval is 0.00357. There are 0 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

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.6224A>G	p.Asn2075Ser	missense	Exon 33 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.6080A>G	p.Asn2027Ser	missense	Exon 33 of 40	NP_001398061.1	A0A804HID9
	SPG11	NM_001160227.2		c.5885A>G	p.Asn1962Ser	missense	Exon 31 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.6224A>G	p.Asn2075Ser	missense	Exon 33 of 40	ENSP00000261866.7	Q96JI7-1
	SPG11	ENST00000535302.6	TSL:1	c.5885A>G	p.Asn1962Ser	missense	Exon 31 of 38	ENSP00000445278.2	Q96JI7-3
	SPG11	ENST00000427534.6	TSL:1	c.6224A>G	p.Asn2075Ser	missense	Exon 33 of 37	ENSP00000396110.2	C4B7M2

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152012 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00396

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00295 AC: 743 AN: 251490 AF XY: 0.00270

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00371 AC: 5419 AN: 1461814 Hom.: 15 Cov.: 32 AF XY: 0.00350 AC XY: 2548 AN XY: 727206

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.00449 AC: 201 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86248

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00429 AC: 4765 AN: 1111960

Other (OTH) AF: 0.00404 AC: 244 AN: 60386

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.00281 AC XY: 209 AN XY: 74362

African (AFR) AF: 0.000843 AC: 35 AN: 41502

American (AMR) AF: 0.00413 AC: 63 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00396 AC: 269 AN: 67988

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00354 Hom.: 5

Bravo AF: 0.00288

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00259 AC: 314

EpiCase AF: 0.00387

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	1	1	Hereditary spastic paraplegia 11 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SPG11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.031
DANN	Benign	0.16
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.53	N
PhyloP100		-0.63
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.085
Sift	Benign	0.49	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.28
MPC		0.032
ClinPred		0.0022	T
GERP RS		-4.8
PromoterAI		-0.0063	Neutral
Varity_R		0.0098
gMVP		0.054
Mutation Taster		=99/1	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: rs140824939; hg19: chr15-44865000; COSMIC: COSV105072602; COSMIC: COSV105072602;