chr15-44567546-C-T

Position:

• chr15-44567546-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 241598.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr15-44567546-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 666 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.6632G>A	p.Arg2211His	missense_variant	36/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.6632G>A	p.Arg2211His	missense_variant	36/40	1	NM_025137.4	ENSP00000261866.7

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

GnomAD3 exomes AF: 0.000815 AC: 205 AN: 251438 Hom.: 0 AF XY: 0.000883 AC XY: 120 AN XY: 135896

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00681

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000920

Gnomad4 OTH exome AF: 0.00149

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

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00102 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SPG11: BP4 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SPG11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;.;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	D;D;T;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0075	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.14	B;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs144165094; hg19: chr15-44859744;